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195-504: 2AS5 , 2A07 93986 114142 ENSG00000128573 ENSMUSG00000029563 O15409 Q75MZ5 Q0PRL4 Q8N6B6 P58463 NM_148900 NM_053242 NM_212435 NM_001286607 NP_683698 NP_001166237.1 NP_683697.2 NP_001273536 NP_444472 NP_997600 Forkhead box protein P2 ( FOXP2 ) is a protein that, in humans, is encoded by the FOXP2 gene . FOXP2

390-520: A carboxyl group, and a variable side chain are bonded . Only proline differs from this basic structure as it contains an unusual ring to the N-end amine group, which forces the CO–NH amide moiety into a fixed conformation. The side chains of the standard amino acids, detailed in the list of standard amino acids , have a great variety of chemical structures and properties; it is the combined effect of all of

585-470: A gene may be duplicated before it can mutate freely. However, this can also lead to complete loss of gene function and thus pseudo-genes . More commonly, single amino acid changes have limited consequences although some can change protein function substantially, especially in enzymes . For instance, many enzymes can change their substrate specificity by one or a few mutations. Changes in substrate specificity are facilitated by substrate promiscuity , i.e.

780-450: A parallel fiber ; the splitting of the vertical branch into two horizontal branches gives rise to a distinctive "T" shape. A human parallel fiber runs for an average of 3 mm in each direction from the split, for a total length of about 6 mm (about 1/10 of the total width of the cortical layer). As they run along, the parallel fibers pass through the dendritic trees of Purkinje cells, contacting one of every 3–5 that they pass, making

975-553: A polyglutamine tract , a zinc finger and a leucine zipper . The protein attaches to the DNA of other proteins and controls their activity through the forkhead-box domain. Only a few targeted genes have been identified, however researchers believe that there could be up to hundreds of other genes targeted by the FOXP2 gene. The forkhead box P2 protein is active in the brain and other tissues before and after birth, and many studies show that it

1170-422: A software algorithm he called a CMAC (Cerebellar Model Articulation Controller), which has been tested in a number of applications. Damage to the cerebellum often causes motor-related symptoms, the details of which depend on the part of the cerebellum involved and how it is damaged. Damage to the flocculonodular lobe may show up as a loss of equilibrium and in particular an altered, irregular walking gait, with

1365-407: A clear association between species with learned vocalizations and similar mutations in FOXP2 . A 2018 analysis of a large sample of globally distributed genomes confirmed there was no evidence of positive selection, suggesting that the original signal of positive selection may be driven by sample composition. Insertion of both human mutations into mice, whose version of FOXP2 otherwise differs from

1560-415: A combination of baseline activity and parallel fiber input. Complex spikes are often followed by a pause of several hundred milliseconds during which simple spike activity is suppressed. A specific, recognizable feature of Purkinje neurons is the expression of calbindin . Calbindin staining of rat brain after unilateral chronic sciatic nerve injury suggests that Purkinje neurons may be newly generated in

1755-552: A combination of sequence, structure and function, and they can be combined in many different ways. In an early study of 170,000 proteins, about two-thirds were assigned at least one domain, with larger proteins containing more domains (e.g. proteins larger than 600 amino acids having an average of more than 5 domains). Most proteins consist of linear polymers built from series of up to 20 different L -α- amino acids. All proteinogenic amino acids possess common structural features, including an α-carbon to which an amino group,

1950-416: A complex pattern reminiscent of the stripes on a zebra. The stripes generated by zebrins and other compartmentalization markers are oriented perpendicular to the cerebellar folds—that is, they are narrow in the mediolateral direction, but much more extended in the longitudinal direction. Different markers generate different sets of stripes, the widths and lengths vary as a function of location, but they all have

2145-401: A critical role in the development of speech and language, this view has been challenged by the fact that the gene is also expressed in other mammals as well as birds and fish that do not speak. It has also been proposed that the FOXP2 transcription-factor is not so much a hypothetical 'language gene' but rather part of a regulatory machinery related to externalization of speech. The FOXP2 gene

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2340-403: A defined conformation . Proteins can interact with many types of molecules, including with other proteins , with lipids , with carbohydrates , and with DNA . It has been estimated that average-sized bacteria contain about 2 million proteins per cell (e.g. E. coli and Staphylococcus aureus ). Smaller bacteria, such as Mycoplasma or spirochetes contain fewer molecules, on

2535-851: A detailed review of the vegetable proteins at the Connecticut Agricultural Experiment Station . Then, working with Lafayette Mendel and applying Liebig's law of the minimum , which states that growth is limited by the scarcest resource, to the feeding of laboratory rats, the nutritionally essential amino acids were established. The work was continued and communicated by William Cumming Rose . The difficulty in purifying proteins in large quantities made them very difficult for early protein biochemists to study. Hence, early studies focused on proteins that could be purified in large quantities, including those of blood, egg whites, and various toxins, as well as digestive and metabolic enzymes obtained from slaughterhouses. In

2730-413: A full understanding of cerebellar function has remained elusive, at least four principles have been identified as important: (1) feedforward processing, (2) divergence and convergence, (3) modularity, and (4) plasticity. There is considerable evidence that the cerebellum plays an essential role in some types of motor learning. The tasks where the cerebellum most clearly comes into play are those in which it

2925-680: A high rate even in the absence of the synaptic input. In awake, behaving animals, mean rates averaging around 40 Hz are typical. The spike trains show a mixture of what are called simple and complex spikes. A simple spike is a single action potential followed by a refractory period of about 10 ms; a complex spike is a stereotyped sequence of action potentials with very short inter-spike intervals and declining amplitudes. Physiological studies have shown that complex spikes (which occur at baseline rates around 1 Hz and never at rates much higher than 10 Hz) are reliably associated with climbing fiber activation, while simple spikes are produced by

3120-436: A larger entity they call a multizonal microcomplex. Such a microcomplex includes several spatially separated cortical microzones, all of which project to the same group of deep cerebellar neurons, plus a group of coupled olivary neurons that project to all of the included microzones as well as to the deep nuclear area. The cerebellum is provided with blood from three paired major arteries: the superior cerebellar artery (SCA),

3315-445: A lesser number of small cells, which use GABA as a neurotransmitter and project exclusively to the inferior olivary nucleus , the source of climbing fibers . Thus, the nucleo-olivary projection provides an inhibitory feedback to match the excitatory projection of climbing fibers to the nuclei. There is evidence that each small cluster of nuclear cells projects to the same cluster of olivary cells that send climbing fibers to it; there

3510-478: A little ambiguous and can overlap in meaning. Protein is generally used to refer to the complete biological molecule in a stable conformation , whereas peptide is generally reserved for a short amino acid oligomers often lacking a stable 3D structure. But the boundary between the two is not well defined and usually lies near 20–30 residues. Polypeptide can refer to any single linear chain of amino acids, usually regardless of length, but often implies an absence of

3705-653: A male is singing to a female usually for a courtship display. "Undirected" singing occurs when for example, a male sings when other males are present or is alone. Studies have found that FoxP2 levels vary depending on the social context. When the birds were singing undirected song, there was a decrease of FoxP2 expression in Area X. This downregulation was not observed and FoxP2 levels remained stable in birds singing directed song. Differences between song-learning and non-song-learning birds have been shown to be caused by differences in FOXP2 gene expression , rather than differences in

3900-497: A member of the neurexin family found in neurons. CNTNAP2 is associated with common forms of language impairment. FOXP2 also downregulates SRPX2 , the 'Sushi Repeat-containing Protein X-linked 2'. It directly reduces its expression, by binding to its gene's promoter . SRPX2 is involved in glutamatergic synapse formation in the cerebral cortex and is more highly expressed in childhood. SRPX2 appears to specifically increase

4095-501: A modest developmental delay. Male mice on encountering female mice produce complex ultrasonic vocalisations that have characteristics of song. Mice that have the R552H point mutation carried by the KE family show cerebellar reduction and abnormal synaptic plasticity in striatal and cerebellar circuits. Humanized FOXP2 mice display altered cortico-basal ganglia circuits. The human allele of

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4290-507: A mossy fiber rosette at its center, and up to 20 granule cell dendritic claws contacting it. Terminals from Golgi cells infiltrate the structure and make inhibitory synapses onto the granule cell dendrites. The entire assemblage is surrounded by a sheath of glial cells. Each mossy fiber sends collateral branches to several cerebellar folia, generating a total of 20–30 rosettes; thus a single mossy fiber makes contact with an estimated 400–600 granule cells. Purkinje cells also receive input from

4485-402: A mouse FOXP2 gene knockouts , loss of both copies of the gene causes severe motor impairment related to cerebellar abnormalities and lack of ultrasonic vocalisations normally elicited when pups are removed from their mothers. These vocalizations have important communicative roles in mother–offspring interactions. Loss of one copy was associated with impairment of ultrasonic vocalisations and

4680-418: A movement, not to initiate movements or to decide which movements to execute. Prior to the 1990s the function of the cerebellum was almost universally believed to be purely motor-related, but newer findings have brought that view into question. Functional imaging studies have shown cerebellar activation in relation to language, attention, and mental imagery; correlation studies have shown interactions between

4875-406: A mutated FOXP2 causes the observed production deficiency. There is some evidence that the linguistic impairments associated with a mutation of the FOXP2 gene are not simply the result of a fundamental deficit in motor control. Brain imaging of affected individuals indicates functional abnormalities in language-related cortical and basal ganglia regions, demonstrating that the problems extend beyond

5070-457: A parallel fiber. Purkinje cells receive more synaptic inputs than any other type of cell in the brain—estimates of the number of spines on a single human Purkinje cell run as high as 200,000. The large, spherical cell bodies of Purkinje cells are packed into a narrow layer (one cell thick) of the cerebellar cortex, called the Purkinje layer . After emitting collaterals that affect nearby parts of

5265-410: A particular cell or cell type is known as its proteome . The chief characteristic of proteins that also allows their diverse set of functions is their ability to bind other molecules specifically and tightly. The region of the protein responsible for binding another molecule is known as the binding site and is often a depression or "pocket" on the molecular surface. This binding ability is mediated by

5460-500: A protein carries out its function: for example, enzyme kinetics studies explore the chemical mechanism of an enzyme's catalytic activity and its relative affinity for various possible substrate molecules. By contrast, in vivo experiments can provide information about the physiological role of a protein in the context of a cell or even a whole organism . In silico studies use computational methods to study proteins. Proteins may be purified from other cellular components using

5655-411: A protein is defined by the sequence of a gene, which is encoded in the genetic code . In general, the genetic code specifies 20 standard amino acids; but in certain organisms the genetic code can include selenocysteine and—in certain archaea — pyrrolysine . Shortly after or even during synthesis, the residues in a protein are often chemically modified by post-translational modification , which alters

5850-542: A protein that fold into distinct structural units. Domains usually also have specific functions, such as enzymatic activities (e.g. kinase ) or they serve as binding modules (e.g. the SH3 domain binds to proline-rich sequences in other proteins). Short amino acid sequences within proteins often act as recognition sites for other proteins. For instance, SH3 domains typically bind to short PxxP motifs (i.e. 2 prolines [P], separated by two unspecified amino acids [x], although

6045-486: A role in biological recognition phenomena involving cells and proteins. Receptors and hormones are highly specific binding proteins. Transmembrane proteins can also serve as ligand transport proteins that alter the permeability of the cell membrane to small molecules and ions. The membrane alone has a hydrophobic core through which polar or charged molecules cannot diffuse . Membrane proteins contain internal channels that allow such molecules to enter and exit

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6240-406: A series of purification steps may be necessary to obtain protein sufficiently pure for laboratory applications. To simplify this process, genetic engineering is often used to add chemical features to proteins that make them easier to purify without affecting their structure or activity. Here, a "tag" consisting of a specific amino acid sequence, often a series of histidine residues (a " His-tag "),

6435-491: A single Purkinje cell. In striking contrast to the 100,000-plus inputs from parallel fibers, each Purkinje cell receives input from exactly one climbing fiber; but this single fiber "climbs" the dendrites of the Purkinje cell, winding around them and making a total of up to 300 synapses as it goes. The net input is so strong that a single action potential from a climbing fiber is capable of producing an extended complex spike in

6630-432: A solution known as a crude lysate . The resulting mixture can be purified using ultracentrifugation , which fractionates the various cellular components into fractions containing soluble proteins; membrane lipids and proteins; cellular organelles , and nucleic acids . Precipitation by a method known as salting out can concentrate the proteins from this lysate. Various types of chromatography are then used to isolate

6825-461: A speech and language disorder called developmental verbal dyspraxia . Their case was studied at the Institute of Child Health of University College London . In 1990, Myrna Gopnik , Professor of Linguistics at McGill University , reported that the disorder-affected KE family had severe speech impediment with incomprehensible talk, largely characterized by grammatical deficits. She hypothesized that

7020-470: A teaching signal that induces synaptic modification in parallel fiber – Purkinje cell synapses. Marr assumed that climbing fiber input would cause synchronously activated parallel fiber inputs to be strengthened. Most subsequent cerebellar-learning models, however, have followed Albus in assuming that climbing fiber activity would be an error signal, and would cause synchronously activated parallel fiber inputs to be weakened. Some of these later models, such as

7215-462: A thick layer at the bottom of the cerebellar cortex. A granule cell emits only four to five dendrites, each of which ends in an enlargement called a dendritic claw . These enlargements are sites of excitatory input from mossy fibers and inhibitory input from Golgi cells . The thin, unmyelinated axons of granule cells rise vertically to the upper (molecular) layer of the cortex, where they split in two, with each branch traveling horizontally to form

7410-399: A total of 80–100 synaptic connections with Purkinje cell dendritic spines. Granule cells use glutamate as their neurotransmitter, and therefore exert excitatory effects on their targets. Granule cells receive all of their input from mossy fibers, but outnumber them by 200 to 1 (in humans). Thus, the information in the granule cell population activity state is the same as the information in

7605-441: A variety of techniques such as ultracentrifugation , precipitation , electrophoresis , and chromatography ; the advent of genetic engineering has made possible a number of methods to facilitate purification. To perform in vitro analysis, a protein must be purified away from other cellular components. This process usually begins with cell lysis , in which a cell's membrane is disrupted and its internal contents released into

7800-459: A very straightforward way. One of the most extensively studied cerebellar learning tasks is the eyeblink conditioning paradigm, in which a neutral conditioned stimulus (CS) such as a tone or a light is repeatedly paired with an unconditioned stimulus (US), such as an air puff, that elicits a blink response. After such repeated presentations of the CS and US, the CS will eventually elicit a blink before

7995-663: A wide stance caused by difficulty in balancing. Damage to the lateral zone typically causes problems in skilled voluntary and planned movements which can cause errors in the force, direction, speed and amplitude of movements. Other manifestations include hypotonia (decreased muscle tone), dysarthria (problems with speech articulation), dysmetria (problems judging distances or ranges of movement), dysdiadochokinesia (inability to perform rapid alternating movements such as walking), impaired check reflex or rebound phenomenon, and intention tremor (involuntary movement caused by alternating contractions of opposing muscle groups). Damage to

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8190-460: Is a little different though largely similar to those of Homo sapiens (i.e. humans). Previous genetic analysis had suggested that the H. sapiens FOXP2 gene became fixed in the population around 125,000 years ago. Some researchers consider the Neanderthal findings to indicate that the gene instead swept through the population over 260,000 years ago, before our most recent common ancestor with

8385-463: Is a member of the forkhead box family of transcription factors , proteins that regulate gene expression by binding to DNA . It is expressed in the brain, heart, lungs and digestive system. FOXP2 is found in many vertebrates , where it plays an important role in mimicry in birds (such as birdsong ) and echolocation in bats. FOXP2 is also required for the proper development of speech and language in humans. In humans, mutations in FOXP2 cause

8580-414: Is attached to one terminus of the protein. As a result, when the lysate is passed over a chromatography column containing nickel , the histidine residues ligate the nickel and attach to the column while the untagged components of the lysate pass unimpeded. A number of different tags have been developed to help researchers purify specific proteins from complex mixtures. Purkinje layer Anatomically,

8775-417: Is best understood as predictive action selection based on "internal models" of the environment or a device for supervised learning , in contrast to the basal ganglia , which perform reinforcement learning , and the cerebral cortex , which performs unsupervised learning . Three decades of brain research have led to the proposal that the cerebellum generates optimized mental models and interacts closely with

8970-440: Is called ataxia . To identify cerebellar problems, neurological examination includes assessment of gait (a broad-based gait being indicative of ataxia), finger-pointing tests and assessment of posture. If cerebellar dysfunction is indicated, a magnetic resonance imaging scan can be used to obtain a detailed picture of any structural alterations that may exist. The list of medical problems that can produce cerebellar damage

9165-561: Is called a folium . High‑resolution MRI finds the adult human cerebellar cortex has an area of 730 square cm, packed within a volume of dimensions 6 cm × 5 cm × 10 cm. Underneath the gray matter of the cortex lies white matter , made up largely of myelinated nerve fibers running to and from the cortex. Embedded within the white matter—which is sometimes called the arbor vitae (tree of life) because of its branched, tree-like appearance in cross-section—are four deep cerebellar nuclei , composed of gray matter. Connecting

9360-562: Is dictated by the nucleotide sequence of their genes , and which usually results in protein folding into a specific 3D structure that determines its activity. A linear chain of amino acid residues is called a polypeptide . A protein contains at least one long polypeptide. Short polypeptides, containing less than 20–30 residues, are rarely considered to be proteins and are commonly called peptides . The individual amino acid residues are bonded together by peptide bonds and adjacent amino acid residues. The sequence of amino acid residues in

9555-628: Is found in hard or filamentous structures such as hair , nails , feathers , hooves , and some animal shells . Some globular proteins can also play structural functions, for example, actin and tubulin are globular and soluble as monomers, but polymerize to form long, stiff fibers that make up the cytoskeleton , which allows the cell to maintain its shape and size. Other proteins that serve structural functions are motor proteins such as myosin , kinesin , and dynein , which are capable of generating mechanical forces. These proteins are crucial for cellular motility of single celled organisms and

9750-469: Is higher in prokaryotes than eukaryotes and can reach up to 20 amino acids per second. The process of synthesizing a protein from an mRNA template is known as translation . The mRNA is loaded onto the ribosome and is read three nucleotides at a time by matching each codon to its base pairing anticodon located on a transfer RNA molecule, which carries the amino acid corresponding to the codon it recognizes. The enzyme aminoacyl tRNA synthetase "charges"

9945-668: Is highly conserved in mammals . The human gene differs from that in non-human primates by the substitution of two amino acids, a threonine to asparagine substitution at position 303 (T303N) and an asparagine to serine substitution at position 325 (N325S). In mice it differs from that of humans by three substitutions, and in zebra finch by seven amino acids. One of the two amino acid differences between human and chimps also arose independently in carnivores and bats. Similar FOXP2 proteins can be found in songbirds , fish , and reptiles such as alligators . DNA sampling from Homo neanderthalensis bones indicates that their FOXP2 gene

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10140-413: Is implicated in motor function learning and maintenance. Through EEG studies, it was also found that these mice had increased levels of activity in their striatum, which contributed to these results. There is further evidence for mutations of targets of the FOXP2 gene shown to have roles in schizophrenia , epilepsy , autism , bipolar disorder and intellectual disabilities. FOXP2 has implications in

10335-461: Is inefficient for polypeptides longer than about 300 amino acids, and the synthesized proteins may not readily assume their native tertiary structure . Most chemical synthesis methods proceed from C-terminus to N-terminus, opposite the biological reaction. Most proteins fold into unique 3D structures. The shape into which a protein naturally folds is known as its native conformation . Although many proteins can fold unassisted, simply through

10530-409: Is known as a language gene. They have delayed onset of speech, difficulty with articulation including slurred speech, stuttering, and poor pronunciation, as well as dyspraxia. It is believed that a major part of this speech deficit comes from an inability to coordinate the movements necessary to produce normal speech including mouth and tongue shaping. Additionally, there are more general impairments with

10725-478: Is known to reliably indicate activity of the cell's climbing fiber input—during periods when performance was poor. Several studies of motor learning in cats observed complex spike activity when there was a mismatch between an intended movement and the movement that was actually executed. Studies of the vestibulo–ocular reflex (which stabilizes the visual image on the retina when the head turns) found that climbing fiber activity indicated "retinal slip", although not in

10920-509: Is localized on a small region of chromosome 7 from DNA samples taken from the affected and unaffected members. The chromosomal region (locus) contained 70 genes. The locus was given the official name "SPCH1" (for speech-and-language-disorder-1) by the Human Genome Nomenclature committee. Mapping and sequencing of the chromosomal region was performed with the aid of bacterial artificial chromosome clones. Around this time,

11115-423: Is long, including stroke , hemorrhage , swelling of the brain ( cerebral edema ), tumors , alcoholism , physical trauma such as gunshot wounds or explosives, and chronic degenerative conditions such as olivopontocerebellar atrophy . Some forms of migraine headache may also produce temporary dysfunction of the cerebellum, of variable severity. Infection can result in cerebellar damage in such conditions as

11310-452: Is necessary to make fine adjustments to the way an action is performed. There has, however, been much dispute about whether learning takes place within the cerebellum itself, or whether it merely serves to provide signals that promote learning in other brain structures. Most theories that assign learning to the circuitry of the cerebellum are derived from the ideas of David Marr and James Albus , who postulated that climbing fibers provide

11505-404: Is often enormous—as much as 10 -fold increase in rate over the uncatalysed reaction in the case of orotate decarboxylase (78 million years without the enzyme, 18 milliseconds with the enzyme). The molecules bound and acted upon by enzymes are called substrates . Although enzymes can consist of hundreds of amino acids, it is usually only a small fraction of the residues that come in contact with

11700-462: Is paramount for the growth of nerve cells and transmission between them. The FOXP2 gene is also involved in synaptic plasticity, making it imperative for learning and memory. FOXP2 is required for proper brain and lung development. Knockout mice with only one functional copy of the FOXP2 gene have significantly reduced vocalizations as pups. Knockout mice with no functional copies of FOXP2 are runted, display abnormalities in brain regions such as

11895-526: Is presumed, performing the same computation. If the input and output connections of a module are with motor areas (as many are), then the module will be involved in motor behavior; but, if the connections are with areas involved in non-motor cognition, the module will show other types of behavioral correlates. Thus the cerebellum has been implicated in the regulation of many differing functional traits such as affection, emotion including emotional body language perception and behavior. The cerebellum, Doya proposes,

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12090-420: Is reversible, the only possible treatment is to help people live with their problems. Visualization of the fetal cerebellum by ultrasound scan at 18 to 20 weeks of pregnancy can be used to screen for fetal neural tube defects with a sensitivity rate of up to 99%. In normal development, endogenous sonic hedgehog signaling stimulates rapid proliferation of cerebellar granule neuron progenitors (CGNPs) in

12285-399: Is strong and matching topography in both directions. When a Purkinje cell axon enters one of the deep nuclei, it branches to make contact with both large and small nuclear cells, but the total number of cells contacted is only about 35 (in cats). Conversely, a single deep nuclear cell receives input from approximately 860 Purkinje cells (again in cats). From the viewpoint of gross anatomy,

12480-591: Is sufficient to derail speech and language development. Protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues . Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions , DNA replication , responding to stimuli , providing structure to cells and organisms , and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which

12675-462: Is that with each granule cell receiving input from only 4–5 mossy fibers, a granule cell would not respond if only a single one of its inputs were active, but would respond if more than one were active. This combinatorial coding scheme would potentially allow the cerebellum to make much finer distinctions between input patterns than the mossy fibers alone would permit. Mossy fibers enter the granular layer from their points of origin, many arising from

12870-486: Is the code for methionine . Because DNA contains four nucleotides, the total number of possible codons is 64; hence, there is some redundancy in the genetic code, with some amino acids specified by more than one codon. Genes encoded in DNA are first transcribed into pre- messenger RNA (mRNA) by proteins such as RNA polymerase . Most organisms then process the pre-mRNA (also known as a primary transcript ) using various forms of post-transcriptional modification to form

13065-476: Is theorized that the translocation of the 7q31.2 region of the FOXP2 gene causes a severe language impairment called developmental verbal dyspraxia (DVD) or childhood apraxia of speech (CAS) So far this type of mutation has only been discovered in three families across the world including the original KE family. A missense mutation causing an arginine-to-histidine substitution (R553H) in the DNA-binding domain

13260-467: Is thought to be involved in planning movement that is about to occur, in evaluating sensory information for action, and in a number of purely cognitive functions, such as determining the verb which best fits with a certain noun (as in "sit" for "chair"). Two types of neuron play dominant roles in the cerebellar circuit: Purkinje cells and granule cells . Three types of axons also play dominant roles: mossy fibers and climbing fibers (which enter

13455-401: Is thought to be the abnormality in KE. This would cause a normally basic residue to be fairly acidic and highly reactive at the body's pH. A heterozygous nonsense mutation, R328X variant, produces a truncated protein involved in speech and language difficulties in one KE individual and two of their close family members. R553H and R328X mutations also affected nuclear localization, DNA-binding, and

13650-509: The Adaptive Filter model of Fujita made attempts to understand cerebellar function in terms of optimal control theory. The idea that climbing fiber activity functions as an error signal has been examined in many experimental studies, with some supporting it but others casting doubt. In a pioneering study by Gilbert and Thach from 1977, Purkinje cells from monkeys learning a reaching task showed increased complex spike activity—which

13845-467: The KE family , FOXP2 was the first gene discovered to be associated with speech and language and was subsequently dubbed "the language gene". However, other genes are necessary for human language development, and a 2018 analysis confirmed that there was no evidence of recent positive evolutionary selection of FOXP2 in humans. As a FOX protein , FOXP2 contains a forkhead-box domain. In addition, it contains

14040-431: The Purkinje layer , and die an average of 21 days after birth from inadequate lung development. FOXP2 is expressed in many areas of the brain, including the basal ganglia and inferior frontal cortex , where it is essential for brain maturation and speech and language development. In mice, the gene was found to be twice as highly expressed in male pups than female pups, which correlated with an almost double increase in

14235-492: The amino acid leucine for which he found a (nearly correct) molecular weight of 131 Da . Early nutritional scientists such as the German Carl von Voit believed that protein was the most important nutrient for maintaining the structure of the body, because it was generally believed that "flesh makes flesh." Around 1862, Karl Heinrich Ritthausen isolated the amino acid glutamic acid . Thomas Burr Osborne compiled

14430-416: The anterior inferior cerebellar artery (AICA), and the posterior inferior cerebellar artery (PICA). The SCA supplies the upper region of the cerebellum. It divides at the upper surface and branches into the pia mater where the branches anastomose with those of the anterior and posterior inferior cerebellar arteries. The AICA supplies the front part of the undersurface of the cerebellum. The PICA arrives at

14625-632: The basal ganglia in songbirds results in incomplete and inaccurate song imitation. Overexpression of FOXP2 was accomplished through injection of adeno-associated virus serotype 1 (AAV1) into area X of the brain. This overexpression produced similar effects to that of knockdown; juvenile zebra finch birds were unable to accurately imitate their tutors. Similarly, in adult canaries, higher FOXP2 levels also correlate with song changes. Levels of FOXP2 in adult zebra finches are significantly higher when males direct their song to females than when they sing song in other contexts. "Directed" singing refers to when

14820-521: The deep cerebellar nuclei . Finally, the axons of basket cells are much longer in the longitudinal direction than in the mediolateral direction, causing them to be confined largely to a single microzone. The consequence of all this structure is that cellular interactions within a microzone are much stronger than interactions between different microzones. In 2005, Richard Apps and Martin Garwicz summarized evidence that microzones themselves form part of

15015-458: The inferior olivary nucleus on the contralateral side of the brainstem via climbing fibers . Although the inferior olive lies in the medulla oblongata and receives input from the spinal cord, brainstem and cerebral cortex, its output goes entirely to the cerebellum. A climbing fiber gives off collaterals to the deep cerebellar nuclei before entering the cerebellar cortex, where it splits into about 10 terminal branches, each of which gives input to

15210-644: The muscle sarcomere , with a molecular mass of almost 3,000 kDa and a total length of almost 27,000 amino acids. Short proteins can also be synthesized chemically by a family of methods known as peptide synthesis , which rely on organic synthesis techniques such as chemical ligation to produce peptides in high yield. Chemical synthesis allows for the introduction of non-natural amino acids into polypeptide chains, such as attachment of fluorescent probes to amino acid side chains. These methods are useful in laboratory biochemistry and cell biology , though generally not for commercial applications. Chemical synthesis

15405-500: The pontine nuclei , others from the spinal cord, vestibular nuclei etc. In the human cerebellum, the total number of mossy fibers has been estimated at 200 million. These fibers form excitatory synapses with the granule cells and the cells of the deep cerebellar nuclei. Within the granular layer, a mossy fiber generates a series of enlargements called rosettes . The contacts between mossy fibers and granule cell dendrites take place within structures called glomeruli . Each glomerulus has

15600-645: The sperm of many multicellular organisms which reproduce sexually . They also generate the forces exerted by contracting muscles and play essential roles in intracellular transport. A key question in molecular biology is how proteins evolve, i.e. how can mutations (or rather changes in amino acid sequence) lead to new structures and functions? Most amino acids in a protein can be changed without disrupting activity or function, as can be seen from numerous homologous proteins across species (as collected in specialized databases for protein families , e.g. PFAM ). In order to prevent dramatic consequences of mutations,

15795-480: The spinal cord (including the spinocerebellar tract ) and from the cranial trigeminal nerve , as well as from visual and auditory systems. It sends fibers to deep cerebellar nuclei that, in turn, project to both the cerebral cortex and the brain stem, thus providing modulation of descending motor systems. The lateral zone, which in humans is by far the largest part, constitutes the cerebrocerebellum, also known as neocerebellum. It receives input exclusively from

15990-415: The vestibular nuclei , although it also receives visual and other sensory input. Damage to this region causes disturbances of balance and gait . The medial zone of the anterior and posterior lobes constitutes the spinocerebellum, also known as paleocerebellum. This sector of the cerebellum functions mainly to fine-tune body and limb movements. It receives proprioceptive input from the dorsal columns of

16185-497: The 1700s by Antoine Fourcroy and others, who often collectively called them " albumins ", or "albuminous materials" ( Eiweisskörper , in German). Gluten , for example, was first separated from wheat in published research around 1747, and later determined to exist in many plants. In 1789, Antoine Fourcroy recognized three distinct varieties of animal proteins: albumin , fibrin , and gelatin . Vegetable (plant) proteins studied in

16380-572: The 1950s, the Armour Hot Dog Company purified 1 kg of pure bovine pancreatic ribonuclease A and made it freely available to scientists; this gesture helped ribonuclease A become a major target for biochemical study for the following decades. The understanding of proteins as polypeptides , or chains of amino acids, came through the work of Franz Hofmeister and Hermann Emil Fischer in 1902. The central role of proteins as enzymes in living organisms that catalyzed reactions

16575-498: The 20,000 or so proteins encoded by the human genome, only 6,000 are detected in lymphoblastoid cells. Proteins are assembled from amino acids using information encoded in genes. Each protein has its own unique amino acid sequence that is specified by the nucleotide sequence of the gene encoding this protein. The genetic code is a set of three-nucleotide sets called codons and each three-nucleotide combination designates an amino acid, for example AUG ( adenine – uracil – guanine )

16770-519: The EC number system provides a functional classification scheme. Similarly, the gene ontology classifies both genes and proteins by their biological and biochemical function, but also by their intracellular location. Sequence similarity is used to classify proteins both in terms of evolutionary and functional similarity. This may use either whole proteins or protein domains , especially in multi-domain proteins . Protein domains allow protein classification by

16965-430: The FOXP2 gene was transferred into the mouse embryos through homologous recombination to create humanized FOXP2 mice. The human variant of FOXP2 also had an effect on the exploratory behavior of the mice. In comparison to knockout mice with one non-functional copy of FOXP2 , the humanized mouse model showed opposite effects when testing its effect on the levels of dopamine, plasticity of synapses, patterns of expression in

17160-466: The Neanderthals. Other researchers offer alternative explanations for how the H. sapiens version would have appeared in Neanderthals living 43,000 years ago. According to a 2002 study, the FOXP2 gene showed indications of recent positive selection . Some researchers have speculated that positive selection is crucial for the evolution of language in humans . Others, however, were unable to find

17355-558: The Purkinje cell: a burst of several spikes in a row, with diminishing amplitude, followed by a pause during which activity is suppressed. The climbing fiber synapses cover the cell body and proximal dendrites; this zone is devoid of parallel fiber inputs. Climbing fibers fire at low rates, but a single climbing fiber action potential induces a burst of several action potentials in a target Purkinje cell (a complex spike). The contrast between parallel fiber and climbing fiber inputs to Purkinje cells (over 100,000 of one type versus exactly one of

17550-480: The US, a conditioned response or CR. Experiments showed that lesions localized either to a specific part of the interposed nucleus (one of the deep cerebellar nuclei) or to a few specific points in the cerebellar cortex would abolish learning of a conditionally timed blink response. If cerebellar outputs are pharmacologically inactivated while leaving the inputs and intracellular circuits intact, learning takes place even while

17745-709: The ability of many enzymes to bind and process multiple substrates . When mutations occur, the specificity of an enzyme can increase (or decrease) and thus its enzymatic activity. Thus, bacteria (or other organisms) can adapt to different food sources, including unnatural substrates such as plastic. Methods commonly used to study protein structure and function include immunohistochemistry , site-directed mutagenesis , X-ray crystallography , nuclear magnetic resonance and mass spectrometry . The activities and structures of proteins may be examined in vitro , in vivo , and in silico . In vitro studies of purified proteins in controlled environments are useful for learning how

17940-405: The addition of a single methyl group to a binding partner can sometimes suffice to nearly eliminate binding; for example, the aminoacyl tRNA synthetase specific to the amino acid valine discriminates against the very similar side chain of the amino acid isoleucine . Proteins can bind to other proteins as well as to small-molecule substrates. When proteins bind specifically to other copies of

18135-436: The adjoining diagram illustrates, Purkinje cell dendrites are flattened in the same direction as the microzones extend, while parallel fibers cross them at right angles. It is not only receptive fields that define the microzone structure: The climbing fiber input from the inferior olivary nucleus is equally important. The branches of a climbing fiber (usually numbering about 10) usually activate Purkinje cells belonging to

18330-417: The adult brain, initiating the organization of new cerebellar lobules. Cerebellar granule cells , in contrast to Purkinje cells, are among the smallest neurons in the brain. They are also the most numerous neurons in the brain: In humans, estimates of their total number average around 50 billion, which means that about 3/4 of the brain's neurons are cerebellar granule cells. Their cell bodies are packed into

18525-413: The affected individuals, but not in unaffected members of the family and other people. This mutation is due to an amino-acid substitution that inhibits the DNA-binding domain of the FOXP2 protein. Further screening of the gene identified multiple additional cases of FOXP2 disruption, including different point mutations and chromosomal rearrangements, providing evidence that damage to one copy of this gene

18720-607: The alpha carbons are roughly coplanar . The other two dihedral angles in the peptide bond determine the local shape assumed by the protein backbone. The end with a free amino group is known as the N-terminus or amino terminus, whereas the end of the protein with a free carboxyl group is known as the C-terminus or carboxy terminus (the sequence of the protein is written from N-terminus to C-terminus, from left to right). The words protein , polypeptide, and peptide are

18915-465: The amino acid sequence of the FOXP2 protein. In zebrafish , FOXP2 is expressed in the ventral and dorsal thalamus , telencephalon , diencephalon where it likely plays a role in nervous system development. The zebrafish FOXP2 gene has an 85% similarity to the human FOX2P ortholog. FOXP2 and its gene were discovered as a result of investigations on an English family known as the KE family , half of whom (15 individuals across three generations) had

19110-531: The amino acid side chains in a protein that ultimately determines its three-dimensional structure and its chemical reactivity. The amino acids in a polypeptide chain are linked by peptide bonds . Once linked in the protein chain, an individual amino acid is called a residue, and the linked series of carbon, nitrogen, and oxygen atoms are known as the main chain or protein backbone. The peptide bond has two resonance forms that contribute some double-bond character and inhibit rotation around its axis, so that

19305-402: The animal fails to show any response, whereas, if intracerebellar circuits are disrupted, no learning takes place—these facts taken together make a strong case that the learning, indeed, occurs inside the cerebellum. The large base of knowledge about the anatomical structure and behavioral functions of the cerebellum have made it a fertile ground for theorizing—there are perhaps more theories of

19500-514: The basis was not of learning or cognitive disability, but due to genetic factors affecting mainly grammatical ability. (Her hypothesis led to a popularised existence of "grammar gene" and a controversial notion of grammar-specific disorder.) In 1995, the University of Oxford and the Institute of Child Health researchers found that the disorder was purely genetic. Remarkably, the inheritance of

19695-574: The binding of a substrate molecule to an enzyme's active site , or the physical region of the protein that participates in chemical catalysis. In solution, proteins also undergo variation in structure through thermal vibration and the collision with other molecules. Proteins can be informally divided into three main classes, which correlate with typical tertiary structures: globular proteins , fibrous proteins , and membrane proteins . Almost all globular proteins are soluble and many are enzymes. Fibrous proteins are often structural, such as collagen ,

19890-570: The body of a multicellular organism. These proteins must have a high binding affinity when their ligand is present in high concentrations, but must also release the ligand when it is present at low concentrations in the target tissues. The canonical example of a ligand-binding protein is haemoglobin , which transports oxygen from the lungs to other organs and tissues in all vertebrates and has close homologs in every biological kingdom . Lectins are sugar-binding proteins which are highly specific for their sugar moieties. Lectins typically play

20085-420: The brain and cerebellar cortex. (The globose and the emboliform nuclei are also referred to as combined in the interposed nucleus ). The fastigial and interposed nuclei belong to the spinocerebellum. The dentate nucleus, which in mammals is much larger than the others, is formed as a thin, convoluted layer of gray matter, and communicates exclusively with the lateral parts of the cerebellar cortex. The flocculus of

20280-558: The cell is as enzymes , which catalyse chemical reactions. Enzymes are usually highly specific and accelerate only one or a few chemical reactions. Enzymes carry out most of the reactions involved in metabolism , as well as manipulating DNA in processes such as DNA replication , DNA repair , and transcription . Some enzymes act on other proteins to add or remove chemical groups in a process known as posttranslational modification. About 4,000 reactions are known to be catalysed by enzymes. The rate acceleration conferred by enzymatic catalysis

20475-436: The cell surface and an effector domain within the cell, which may have enzymatic activity or may undergo a conformational change detected by other proteins within the cell. Antibodies are protein components of an adaptive immune system whose main function is to bind antigens , or foreign substances in the body, and target them for destruction. Antibodies can be secreted into the extracellular environment or anchored in

20670-752: The cell's machinery through the process of protein turnover . A protein's lifespan is measured in terms of its half-life and covers a wide range. They can exist for minutes or years with an average lifespan of 1–2 days in mammalian cells. Abnormal or misfolded proteins are degraded more rapidly either due to being targeted for destruction or due to being unstable. Like other biological macromolecules such as polysaccharides and nucleic acids , proteins are essential parts of organisms and participate in virtually every process within cells . Many proteins are enzymes that catalyse biochemical reactions and are vital to metabolism . Proteins also have structural or mechanical functions, such as actin and myosin in muscle and

20865-450: The cell. Many ion channel proteins are specialized to select for only a particular ion; for example, potassium and sodium channels often discriminate for only one of the two ions. Structural proteins confer stiffness and rigidity to otherwise-fluid biological components. Most structural proteins are fibrous proteins ; for example, collagen and elastin are critical components of connective tissue such as cartilage , and keratin

21060-488: The cerebellar cortex appears to be a homogeneous sheet of tissue, and, from the viewpoint of microanatomy, all parts of this sheet appear to have the same internal structure. There are, however, a number of respects in which the structure of the cerebellum is compartmentalized. There are large compartments that are generally known as zones ; these can be divided into smaller compartments known as microzones . The first indications of compartmental structure came from studies of

21255-405: The cerebellar cortex is interconnected with association zones of the cerebral cortex. Kenji Doya has argued that the cerebellum's function is best understood not in terms of the behaviors it affects, but the neural computations it performs; the cerebellum consists of a large number of more or less independent modules, all with the same geometrically regular internal structure, and therefore all, it

21450-471: The cerebellar cortex is the molecular layer. This layer contains the flattened dendritic trees of Purkinje cells, and the huge array of parallel fibers, from the granular layer, that penetrate the Purkinje cell dendritic trees at right angles. The molecular layer also contains two types of inhibitory interneuron: stellate cells and basket cells . Both stellate and basket cells form GABAergic synapses onto Purkinje cell dendrites. Purkinje cells are among

21645-428: The cerebellum and non-motor areas of the cerebral cortex; and a variety of non-motor symptoms have been recognized in people with damage that appears to be confined to the cerebellum. In particular, the cerebellar cognitive affective syndrome or Schmahmann's syndrome has been described in adults and children. Estimates based on functional mapping of the cerebellum using functional MRI suggest that more than half of

21840-523: The cerebellum can be parsed functionally into a medial sector called the spinocerebellum and a larger lateral sector called the cerebrocerebellum . A narrow strip of protruding tissue along the midline is called the cerebellar vermis . ( Vermis is Latin for "worm".) The smallest region, the flocculonodular lobe, is often called the vestibulocerebellum . It is the oldest part in evolutionary terms (archicerebellum) and participates mainly in balance and spatial orientation; its primary connections are with

22035-518: The cerebellum from outside), and parallel fibers (which are the axons of granule cells). There are two main pathways through the cerebellar circuit, originating from mossy fibers and climbing fibers, both eventually terminating in the deep cerebellar nuclei. Mossy fibers project directly to the deep nuclei, but also give rise to the following pathway: mossy fibers → granule cells → parallel fibers → Purkinje cells → deep nuclei. Climbing fibers project to Purkinje cells and also send collaterals directly to

22230-550: The cerebellum functions essentially as a timing system has also been advocated by Richard Ivry . Another influential "performance" theory is the Tensor network theory of Pellionisz and Llinás , which provided an advanced mathematical formulation of the idea that the fundamental computation performed by the cerebellum is to transform sensory into motor coordinates. Theories in the "learning" category almost all derive from publications by Marr and Albus. Marr's 1969 paper proposed that

22425-596: The cerebellum is a device for learning to associate elemental movements encoded by climbing fibers with mossy fiber inputs that encode the sensory context. Albus proposed in 1971 that a cerebellar Purkinje cell functions as a perceptron , a neurally inspired abstract learning device. The most basic difference between the Marr and Albus theories is that Marr assumed that climbing fiber activity would cause parallel fiber synapses to be strengthened, whereas Albus proposed that they would be weakened. Albus also formulated his version as

22620-429: The cerebellum is divided into two cerebellar hemispheres ; it also contains a narrow midline zone (the vermis ). A set of large folds is, by convention, used to divide the overall structure into 10 smaller "lobules". Because of its large number of tiny granule cells , the cerebellum contains more neurons than the total from the rest of the brain, but takes up only 10% of the total brain volume. The number of neurons in

22815-431: The cerebellum is related to the number of neurons in the neocortex . There are about 3.6 times as many neurons in the cerebellum as in the neocortex, a ratio that is conserved across many different mammalian species. The unusual surface appearance of the cerebellum conceals the fact that most of its volume is made up of a very tightly folded layer of gray matter : the cerebellar cortex . Each ridge or gyrus in this layer

23010-415: The cerebellum to different parts of the nervous system are three paired cerebellar peduncles . These are the superior cerebellar peduncle , the middle cerebellar peduncle and the inferior cerebellar peduncle , named by their position relative to the vermis. The superior cerebellar peduncle is mainly an output to the cerebral cortex, carrying efferent fibers via thalamic nuclei to upper motor neurons in

23205-436: The cerebellum. In addition to its direct role in motor control, the cerebellum is necessary for several types of motor learning , most notably learning to adjust to changes in sensorimotor relationships . Several theoretical models have been developed to explain sensorimotor calibration in terms of synaptic plasticity within the cerebellum. These models derive from those formulated by David Marr and James Albus , based on

23400-405: The cerebellum. It is separated from the overlying cerebrum by a layer of leathery dura mater , the cerebellar tentorium ; all of its connections with other parts of the brain travel through the pons. Anatomists classify the cerebellum as part of the metencephalon , which also includes the pons; the metencephalon is the upper part of the rhombencephalon or "hindbrain". Like the cerebral cortex,

23595-458: The cerebellum. The inferior cerebellar peduncle receives input from afferent fibers from the vestibular nuclei, spinal cord and the tegmentum. Output from the inferior peduncle is via efferent fibers to the vestibular nuclei and the reticular formation. The whole of the cerebellum receives modulatory input from the inferior olivary nucleus via the inferior cerebellar peduncle. Based on the surface appearance, three lobes can be distinguished within

23790-455: The cerebellum: the anterior lobe (above the primary fissure ), the posterior lobe (below the primary fissure), and the flocculonodular lobe (below the posterior fissure). These lobes divide the cerebellum from rostral to caudal (in humans, top to bottom). In terms of function, however, there is a more important distinction along the medial-to-lateral dimension. Leaving out the flocculonodular lobe, which has distinct connections and functions,

23985-410: The cerebral cortex (especially the parietal lobe ) via the pontine nuclei (forming cortico-ponto-cerebellar pathways), and sends output mainly to the ventrolateral thalamus (in turn connected to motor areas of the premotor cortex and primary motor area of the cerebral cortex) and to the red nucleus . There is disagreement about the best way to describe the functions of the lateral cerebellum: It

24180-459: The cerebral cortex, where updated internal models are experienced as creative intuition ("a ha") in working memory. The comparative simplicity and regularity of the cerebellar anatomy led to an early hope that it might imply a similar simplicity of computational function, as expressed in one of the first books on cerebellar electrophysiology, The Cerebellum as a Neuronal Machine by John C. Eccles , Masao Ito , and János Szentágothai . Although

24375-498: The cerebral cortex. The fibers arise from the deep cerebellar nuclei. The middle cerebellar peduncle is connected to the pons and receives all of its input from the pons mainly from the pontine nuclei . The input to the pons is from the cerebral cortex and is relayed from the pontine nuclei via transverse pontine fibers to the cerebellum. The middle peduncle is the largest of the three and its afferent fibers are grouped into three separate fascicles taking their inputs to different parts of

24570-621: The chemical properties of their amino acids, others require the aid of molecular chaperones to fold into their native states. Biochemists often refer to four distinct aspects of a protein's structure: Proteins are not entirely rigid molecules. In addition to these levels of structure, proteins may shift between several related structures while they perform their functions. In the context of these functional rearrangements, these tertiary or quaternary structures are usually referred to as " conformations ", and transitions between them are called conformational changes. Such changes are often induced by

24765-441: The chief actors within the cell, said to be carrying out the duties specified by the information encoded in genes. With the exception of certain types of RNA , most other biological molecules are relatively inert elements upon which proteins act. Proteins make up half the dry weight of an Escherichia coli cell, whereas other macromolecules such as DNA and RNA make up only 3% and 20%, respectively. The set of proteins expressed in

24960-404: The climbing fibers signal errors in motor performance, either in the usual manner of discharge frequency modulation or as a single announcement of an 'unexpected event'. For other investigators, the message lies in the degree of ensemble synchrony and rhythmicity among a population of climbing fibers." The deep nuclei of the cerebellum are clusters of gray matter lying within the white matter at

25155-399: The consequences of damage to it. Animals and humans with cerebellar dysfunction show, above all, problems with motor control, on the same side of the body as the damaged part of the cerebellum. They continue to be able to generate motor activity but lose precision, producing erratic, uncoordinated, or incorrectly timed movements. A standard test of cerebellar function is to reach with the tip of

25350-490: The construction of enormously complex signaling networks. As interactions between proteins are reversible, and depend heavily on the availability of different groups of partner proteins to form aggregates that are capable to carry out discrete sets of function, study of the interactions between specific proteins is a key to understand important aspects of cellular function, and ultimately the properties that distinguish particular cell types. The best-known role of proteins in

25545-416: The core of the cerebellum. They are, with the minor exception of the nearby vestibular nuclei, the sole sources of output from the cerebellum. These nuclei receive collateral projections from mossy fibers and climbing fibers as well as inhibitory input from the Purkinje cells of the cerebellar cortex. The four nuclei ( dentate , globose , emboliform , and fastigial ) each communicate with different parts of

25740-584: The cortex, their axons travel into the deep cerebellar nuclei , where they make on the order of 1,000 contacts each with several types of nuclear cells, all within a small domain. Purkinje cells use GABA as their neurotransmitter, and therefore exert inhibitory effects on their targets. Purkinje cells form the heart of the cerebellar circuit, and their large size and distinctive activity patterns have made it relatively easy to study their response patterns in behaving animals using extracellular recording techniques. Purkinje cells normally emit action potentials at

25935-492: The deep nuclei. The mossy fiber and climbing fiber inputs each carry fiber-specific information; the cerebellum also receives dopaminergic , serotonergic , noradrenergic , and cholinergic inputs that presumably perform global modulation. The cerebellar cortex is divided into three layers. At the bottom lies the thick granular layer, densely packed with granule cells, along with interneurons , mainly Golgi cells but also including Lugaro cells and unipolar brush cells . In

26130-408: The derivative unit kilodalton (kDa). The average size of a protein increases from Archaea to Bacteria to Eukaryote (283, 311, 438 residues and 31, 34, 49 kDa respectively) due to a bigger number of protein domains constituting proteins in higher organisms. For instance, yeast proteins are on average 466 amino acids long and 53 kDa in mass. The largest known proteins are the titins , a component of

26325-695: The development of bat echolocation . Contrary to apes and mice, FOXP2 is extremely diverse in echolocating bats . Twenty-two sequences of non-bat eutherian mammals revealed a total number of 20 nonsynonymous mutations in contrast to half that number of bat sequences, which showed 44 nonsynonymous mutations. All cetaceans share three amino acid substitutions, but no differences were found between echolocating toothed whales and non-echolocating baleen cetaceans . Within bats, however, amino acid variation correlated with different echolocating types. In songbirds , FOXP2 most likely regulates genes involved in neuroplasticity . Gene knockdown of FOXP2 in area X of

26520-610: The disorder from one generation to the next was consistent with autosomal dominant inheritance, i.e., mutation of only a single gene on an autosome (non- sex chromosome ) acting in a dominant fashion. This is one of the few known examples of Mendelian (monogenic) inheritance for a disorder affecting speech and language skills, which typically have a complex basis involving multiple genetic risk factors. In 1998, Oxford University geneticists Simon Fisher , Anthony Monaco , Cecilia S. L. Lai, Jane A. Hurst, and Faraneh Vargha-Khadem identified an autosomal dominant monogenic inheritance that

26715-481: The earliest "performance" theory was the "delay line" hypothesis of Valentino Braitenberg . The original theory put forth by Braitenberg and Roger Atwood in 1958 proposed that slow propagation of signals along parallel fibers imposes predictable delays that allow the cerebellum to detect time relationships within a certain window. Experimental data did not support the original form of the theory, but Braitenberg continued to argue for modified versions. The hypothesis that

26910-451: The erroneous conclusion that they might be composed of a single type of (very large) molecule. The term "protein" to describe these molecules was proposed by Mulder's associate Berzelius; protein is derived from the Greek word πρώτειος ( proteios ), meaning "primary", "in the lead", or "standing in front", + -in . Mulder went on to identify the products of protein degradation such as

27105-490: The external granule layer (EGL). Cerebellar development occurs during late embryogenesis and the early postnatal period, with CGNP proliferation in the EGL peaking during early development (postnatal day 7 in the mouse). As CGNPs terminally differentiate into cerebellar granule cells (also called cerebellar granule neurons, CGNs), they migrate to the internal granule layer (IGL), forming the mature cerebellum (by post-natal day 20 in

27300-415: The finger for a target at arm's length: A healthy person will move the fingertip in a rapid straight trajectory, whereas a person with cerebellar damage will reach slowly and erratically, with many mid-course corrections. Deficits in non-motor functions are more difficult to detect. Thus, the general conclusion reached decades ago is that the basic function of the cerebellum is to calibrate the detailed form of

27495-432: The flocculonodular lobe is the only part of the cerebellar cortex that does not project to the deep nuclei—its output goes to the vestibular nuclei instead. The majority of neurons in the deep nuclei have large cell bodies and spherical dendritic trees with a radius of about 400 μm, and use glutamate as their neurotransmitter. These cells project to a variety of targets outside the cerebellum. Intermixed with them are

27690-505: The function of the cerebellum than of any other part of the brain. The most basic distinction among them is between "learning theories" and "performance theories"—that is, theories that make use of synaptic plasticity within the cerebellum to account for its role in learning, versus theories that account for aspects of ongoing behavior on the basis of cerebellar signal processing. Several theories of both types have been formulated as mathematical models and simulated using computers. Perhaps

27885-437: The human and chimpanzee versions in only one additional base pair, causes changes in vocalizations as well as other behavioral changes, such as a reduction in exploratory tendencies, and a decrease in maze learning time. A reduction in dopamine levels and changes in the morphology of certain nerve cells are also observed. FOXP2 is known to regulate CNTNAP2 , CTBP1 , SRPX2 and SCN3A . FOXP2 downregulates CNTNAP2 ,

28080-434: The human cerebellum has the appearance of a separate structure attached to the bottom of the brain, tucked underneath the cerebral hemispheres . Its cortical surface is covered with finely spaced parallel grooves, in striking contrast to the broad irregular convolutions of the cerebral cortex . These parallel grooves conceal the fact that the cerebellar cortex is actually a thin, continuous layer of tissue tightly folded in

28275-417: The human cerebellum show less age-related alteration than that in the cerebral cortex . Some studies have reported reductions in numbers of cells or volume of tissue, but the amount of data relating to this question is not very large. Congenital malformation, hereditary disorders, and acquired conditions can affect cerebellar structure and, consequently, cerebellar function. Unless the causative condition

28470-534: The late 1700s and early 1800s included gluten , plant albumin , gliadin , and legumin . Proteins were first described by the Dutch chemist Gerardus Johannes Mulder and named by the Swedish chemist Jöns Jacob Berzelius in 1838. Mulder carried out elemental analysis of common proteins and found that nearly all proteins had the same empirical formula , C 400 H 620 N 100 O 120 P 1 S 1 . He came to

28665-478: The major component of connective tissue, or keratin , the protein component of hair and nails. Membrane proteins often serve as receptors or provide channels for polar or charged molecules to pass through the cell membrane . A special case of intramolecular hydrogen bonds within proteins, poorly shielded from water attack and hence promoting their own dehydration , are called dehydrons . Many proteins are composed of several protein domains , i.e. segments of

28860-443: The mature mRNA, which is then used as a template for protein synthesis by the ribosome . In prokaryotes the mRNA may either be used as soon as it is produced, or be bound by a ribosome after having moved away from the nucleoid . In contrast, eukaryotes make mRNA in the cell nucleus and then translocate it across the nuclear membrane into the cytoplasm , where protein synthesis then takes place. The rate of protein synthesis

29055-405: The membranes of specialized B cells known as plasma cells . Whereas enzymes are limited in their binding affinity for their substrates by the necessity of conducting their reaction, antibodies have no such constraints. An antibody's binding affinity to its target is extraordinarily high. Many ligand transport proteins bind particular small biomolecules and transport them to other locations in

29250-588: The middle lies the Purkinje layer, a narrow zone that contains the cell bodies of Purkinje cells and Bergmann glial cells . At the top lies the molecular layer, which contains the flattened dendritic trees of Purkinje cells, along with the huge array of parallel fibers penetrating the Purkinje cell dendritic trees at right angles. This outermost layer of the cerebellar cortex also contains two types of inhibitory interneuron: stellate cells and basket cells . Both stellate and basket cells form GABAergic synapses onto Purkinje cell dendrites. The top, outermost layer of

29445-452: The midline portion may disrupt whole-body movements, whereas damage localized more laterally is more likely to disrupt fine movements of the hands or limbs. Damage to the upper part of the cerebellum tends to cause gait impairments and other problems with leg coordination; damage to the lower part is more likely to cause uncoordinated or poorly aimed movements of the arms and hands, as well as difficulties in speed. This complex of motor symptoms

29640-406: The mossy fibers, but recoded in a much more expansive way. Because granule cells are so small and so densely packed, it is difficult to record their spike activity in behaving animals, so there is little data to use as a basis for theorizing. The most popular concept of their function was proposed in 1969 by David Marr , who suggested that they could encode combinations of mossy fiber inputs. The idea

29835-611: The most distinctive neurons in the brain, and one of the earliest types to be recognized—they were first described by the Czech anatomist Jan Evangelista Purkyně in 1837. They are distinguished by the shape of their dendritic tree: the dendrites branch very profusely, but are severely flattened in a plane perpendicular to the cerebellar folds. Thus, the dendrites of a Purkinje cell form a dense planar net, through which parallel fibers pass at right angles. The dendrites are covered with dendritic spines , each of which receives synaptic input from

30030-452: The motor system. Mutations in FOXP2 are among several (26 genes plus 2 intergenic) loci which correlate to ADHD diagnosis in adults – clinical ADHD is an umbrella label for a heterogeneous group of genetic and neurological phenomena which may result from FOXP2 mutations or other causes. A 2020 genome-wide association study (GWAS) implicates single-nucleotide polymorphisms (SNPs) of FOXP2 in susceptibility to cannabis use disorder . It

30225-421: The mouse brain, which is the processing area that auditory inputs must go through in the thalamus. It was found that its mutations play a role in delaying the development of language learning. It was also found to be highly expressed in the Purkinje cells and cerebellar nuclei of the cortico-cerebellar circuits. High FOXP2 expression has also been shown in the spiny neurons that express type 1 dopamine receptors in

30420-710: The mouse). Mutations that abnormally activate Sonic hedgehog signaling predispose to cancer of the cerebellum ( medulloblastoma ) in humans with Gorlin Syndrome and in genetically engineered mouse models . Congenital malformation or underdevelopment ( hypoplasia ) of the cerebellar vermis is a characteristic of both Dandy–Walker syndrome and Joubert syndrome . In very rare cases, the entire cerebellum may be absent . The inherited neurological disorders Machado–Joseph disease , ataxia telangiectasia , and Friedreich's ataxia cause progressive neurodegeneration linked to cerebellar loss. Congenital brain malformations outside

30615-426: The mutation is in the middle of a protein-coding gene. Using a combination of bioinformatics and RNA analyses, they discovered that the gene codes for a novel protein belonging to the forkhead-box (FOX) group of transcription factors . As such, it was assigned with the official name of FOXP2. When the researchers sequenced the FOXP2 gene in the KE family, they found a heterozygous point mutation shared by all

30810-447: The neural functions of FOXP2 . The FOXP2 gene has been implicated in several cognitive functions including; general brain development, language, and synaptic plasticity. The FOXP2 gene region acts as a transcription factor for the forkhead box P2 protein. Transcription factors affect other regions, and the forkhead box P2 protein has been suggested to also act as a transcription factor for hundreds of genes. This prolific involvement opens

31005-496: The nobel prize in 1972, solidified the thermodynamic hypothesis of protein folding, according to which the folded form of a protein represents its free energy minimum. With the development of X-ray crystallography , it became possible to determine protein structures as well as their sequences. The first protein structures to be solved were hemoglobin by Max Perutz and myoglobin by John Kendrew , in 1958. The use of computers and increasing computing power also supported

31200-603: The number of glutamatergic synapses in the brain, while leaving inhibitory GABAergic synapses unchanged and not affecting dendritic spine length or shape. On the other hand, FOXP2's activity does reduce dendritic spine length and shape, in addition to number, indicating it has other regulatory roles in dendritic morphology. In chimpanzees, FOXP2 differs from the human version by two amino acids. A study in Germany sequenced FOXP2's complementary DNA in chimps and other species to compare it with human complementary DNA in order to find

31395-459: The number of vocalisations the male pups made when separated from mothers. Conversely, in human children aged 4–5, the gene was found to be 30% more expressed in the Broca's areas of female children. The researchers suggested that the gene is more active in "the more communicative sex". The expression of FOXP2 is subject to post-transcriptional regulation , particularly microRNA (miRNA), causing

31590-456: The observation that each cerebellar Purkinje cell receives two dramatically different types of input: one comprises thousands of weak inputs from the parallel fibers of the granule cells; the other is an extremely strong input from a single climbing fiber . The basic concept of the Marr–Albus theory is that the climbing fiber serves as a "teaching signal", which induces a long-lasting change in

31785-500: The order of 50,000 to 1 million. By contrast, eukaryotic cells are larger and thus contain much more protein. For instance, yeast cells have been estimated to contain about 50 million proteins and human cells on the order of 1 to 3 billion. The concentration of individual protein copies ranges from a few molecules per cell up to 20 million. Not all genes coding proteins are expressed in most cells and their number depends on, for example, cell type and external stimuli. For instance, of

31980-510: The other type) is perhaps the most provocative feature of cerebellar anatomy, and has motivated much of the theorizing. In fact, the function of climbing fibers is the most controversial topic concerning the cerebellum. There are two schools of thought, one following Marr and Albus in holding that climbing fiber input serves primarily as a teaching signal, the other holding that its function is to shape cerebellar output directly. Both views have been defended in great length in numerous publications. In

32175-440: The physical and chemical properties, folding, stability, activity, and ultimately, the function of the proteins. Some proteins have non-peptide groups attached, which can be called prosthetic groups or cofactors . Proteins can also work together to achieve a particular function, and they often associate to form stable protein complexes . Once formed, proteins only exist for a certain period and are then degraded and recycled by

32370-434: The possibility that the FOXP2 gene is much more extensive than originally thought. Other targets of transcription have been researched without correlation to FOXP2. Specifically, FOXP2 has been investigated in correlation with autism and dyslexia, however with no mutation was discovered as the cause. One well identified target is language. Although some research disagrees with this correlation, the majority of research shows that

32565-451: The prion diseases and Miller Fisher syndrome, a variant of Guillain–Barré syndrome . The human cerebellum changes with age. These changes may differ from those of other parts of the brain. The cerebellum is the youngest brain region (and body part) in centenarians according to an epigenetic biomarker of tissue age known as epigenetic clock : it is about 15 years younger than expected in a centenarian. Further, gene expression patterns in

32760-424: The process of cell signaling and signal transduction . Some proteins, such as insulin , are extracellular proteins that transmit a signal from the cell in which they were synthesized to other cells in distant tissues . Others are membrane proteins that act as receptors whose main function is to bind a signaling molecule and induce a biochemical response in the cell. Many receptors have a binding site exposed on

32955-430: The processing of the grammatical and linguistic aspects of speech. These findings suggest that the effects of FOXP2 are not limited to motor control, as they include comprehension among other cognitive language functions. General mild motor and cognitive deficits are noted across the board. Clinically these patients can also have difficulty coughing, sneezing, or clearing their throats. While FOXP2 has been proposed to play

33150-534: The protein or proteins of interest based on properties such as molecular weight, net charge and binding affinity. The level of purification can be monitored using various types of gel electrophoresis if the desired protein's molecular weight and isoelectric point are known, by spectroscopy if the protein has distinguishable spectroscopic features, or by enzyme assays if the protein has enzymatic activity. Additionally, proteins can be isolated according to their charge using electrofocusing . For natural proteins,

33345-427: The proteins in the cytoskeleton , which form a system of scaffolding that maintains cell shape. Other proteins are important in cell signaling, immune responses , cell adhesion , and the cell cycle . In animals, proteins are needed in the diet to provide the essential amino acids that cannot be synthesized . Digestion breaks the proteins down for metabolic use. Proteins have been studied and recognized since

33540-469: The receptive fields of cells in various parts of the cerebellar cortex. Each body part maps to specific points in the cerebellum, but there are numerous repetitions of the basic map, forming an arrangement that has been called "fractured somatotopy". A clearer indication of compartmentalization is obtained by immunostaining the cerebellum for certain types of protein. The best-known of these markers are called "zebrins", because staining for them gives rise to

33735-414: The repression of the FOXP2 3' untranslated region . Three amino acid substitutions distinguish the human FOXP2 protein from that found in mice, while two amino acid substitutions distinguish the human FOXP2 protein from that found in chimpanzees, but only one of these changes is unique to humans. Evidence from genetically manipulated mice and human neuronal cell models suggests that these changes affect

33930-471: The researchers identified an individual who was unrelated to the KE family but had a similar type of speech and language disorder. In this case, the child, known as CS, carried a chromosomal rearrangement (a translocation ) in which part of chromosome 7 had become exchanged with part of chromosome 5. The site of breakage of chromosome 7 was located within the SPCH1 region. In 2001, the team identified in CS that

34125-413: The same general shape. Oscarsson in the late 1970s proposed that these cortical zones can be partitioned into smaller units called microzones. A microzone is defined as a group of Purkinje cells all having the same somatotopic receptive field. Microzones were found to contain on the order of 1000 Purkinje cells each, arranged in a long, narrow strip, oriented perpendicular to the cortical folds. Thus, as

34320-400: The same microzone. Moreover, olivary neurons that send climbing fibers to the same microzone tend to be coupled by gap junctions , which synchronize their activity, causing Purkinje cells within a microzone to show correlated complex spike activity on a millisecond time scale. Also, the Purkinje cells belonging to a microzone all send their axons to the same small cluster of output cells within

34515-582: The same molecule, they can oligomerize to form fibrils; this process occurs often in structural proteins that consist of globular monomers that self-associate to form rigid fibers. Protein–protein interactions also regulate enzymatic activity, control progression through the cell cycle , and allow the assembly of large protein complexes that carry out many closely related reactions with a common biological function. Proteins can also bind to, or even be integrated into, cell membranes. The ability of binding partners to induce conformational changes in proteins allows

34710-581: The sample, allowing scientists to obtain more information and analyze larger structures. Computational protein structure prediction of small protein structural domains has also helped researchers to approach atomic-level resolution of protein structures. As of April 2024 , the Protein Data Bank contains 181,018 X-ray, 19,809 EM and 12,697 NMR protein structures. Proteins are primarily classified by sequence and structure, although other classifications are commonly used. Especially for enzymes

34905-430: The sequencing of complex proteins. In 1999, Roger Kornberg succeeded in sequencing the highly complex structure of RNA polymerase using high intensity X-rays from synchrotrons . Since then, cryo-electron microscopy (cryo-EM) of large macromolecular assemblies has been developed. Cryo-EM uses protein samples that are frozen rather than crystals, and beams of electrons rather than X-rays. It causes less damage to

35100-426: The severe speech and language disorder developmental verbal dyspraxia . Studies of the gene in mice and songbirds indicate that it is necessary for vocal imitation and the related motor learning. Outside the brain, FOXP2 has also been implicated in development of other tissues such as the lung and digestive system. Initially identified in 1998 as the genetic cause of a speech disorder in a British family designated

35295-406: The specific changes in the sequence. FOXP2 was found to be functionally different in humans compared to chimps. Since FOXP2 was also found to have an effect on other genes, its effects on other genes is also being studied. Researchers deduced that there could also be further clinical applications in the direction of these studies in regards to illnesses that show effects on human language ability. In

35490-418: The strength of parallel fiber inputs. Observations of long-term depression in parallel fiber inputs have provided some support for theories of this type, but their validity remains controversial. At the level of gross anatomy , the cerebellum consists of a tightly folded layer of cortex , with white matter underneath and a fluid-filled ventricle at the base. Four deep cerebellar nuclei are embedded in

35685-432: The striatum and behavior that was exploratory in nature. When FOXP2 expression was altered in mice, it affected many different processes including the learning motor skills and the plasticity of synapses. Additionally, FOXP2 is found more in the sixth layer of the cortex than in the fifth , and this is consistent with it having greater roles in sensory integration. FOXP2 was also found in the medial geniculate nucleus of

35880-408: The striatum, substantia nigra , subthalamic nucleus and ventral tegmental area . The negative effects of the mutations of FOXP2 in these brain regions on motor abilities were shown in mice through tasks in lab studies. When analyzing the brain circuitry in these cases, scientists found greater levels of dopamine and decreased lengths of dendrites, which caused defects in long-term depression , which

36075-407: The style of an accordion . Within this thin layer are several types of neurons with a highly regular arrangement, the most important being Purkinje cells and granule cells . This complex neural organization gives rise to a massive signal-processing capability, but almost all of the output from the cerebellar cortex passes through a set of small deep nuclei lying in the white matter interior of

36270-405: The substrate, and an even smaller fraction—three to four residues on average—that are directly involved in catalysis. The region of the enzyme that binds the substrate and contains the catalytic residues is known as the active site . Dirigent proteins are members of a class of proteins that dictate the stereochemistry of a compound synthesized by other enzymes. Many proteins are involved in

36465-716: The surrounding amino acids may determine the exact binding specificity). Many such motifs has been collected in the Eukaryotic Linear Motif (ELM) database. Topology of a protein describes the entanglement of the backbone and the arrangement of contacts within the folded chain. Two theoretical frameworks of knot theory and Circuit topology have been applied to characterise protein topology. Being able to describe protein topology opens up new pathways for protein engineering and pharmaceutical development, and adds to our understanding of protein misfolding diseases such as neuromuscular disorders and cancer. Proteins are

36660-400: The tRNA molecules with the correct amino acids. The growing polypeptide is often termed the nascent chain . Proteins are always biosynthesized from N-terminus to C-terminus . The size of a synthesized protein can be measured by the number of amino acids it contains and by its total molecular mass , which is normally reported in units of daltons (synonymous with atomic mass units ), or

36855-472: The tertiary structure of the protein, which defines the binding site pocket, and by the chemical properties of the surrounding amino acids' side chains. Protein binding can be extraordinarily tight and specific; for example, the ribonuclease inhibitor protein binds to human angiogenin with a sub-femtomolar dissociation constant (<10 M) but does not bind at all to its amphibian homolog onconase (> 1 M). Extremely minor chemical changes such as

37050-414: The transactivation (increased gene expression) properties of FOXP2. These individuals present with deletions, translocations, and missense mutations. When tasked with repetition and verb generation, these individuals with DVD/CAS had decreased activation in the putamen and Broca's area in fMRI studies. These areas are commonly known as areas of language function. This is one of the primary reasons that FOXP2

37245-515: The undersurface, where it divides into a medial branch and a lateral branch. The medial branch continues backward to the cerebellar notch between the two hemispheres of the cerebellum; while the lateral branch supplies the under surface of the cerebellum, as far as its lateral border, where it anastomoses with the AICA and the SCA. The strongest clues to the function of the cerebellum have come from examining

37440-459: The white matter. Each part of the cortex consists of the same small set of neuronal elements, laid out in a highly stereotyped geometry. At an intermediate level, the cerebellum and its auxiliary structures can be separated into several hundred or thousand independently functioning modules called "microzones" or "microcompartments". The cerebellum is located in the posterior cranial fossa . The fourth ventricle , pons and medulla are in front of

37635-405: The words of one review, "In trying to synthesize the various hypotheses on the function of the climbing fibers, one has the sense of looking at a drawing by Escher. Each point of view seems to account for a certain collection of findings, but when one attempts to put the different views together, a coherent picture of what the climbing fibers are doing does not appear. For the majority of researchers,

37830-472: Was insulin , by Frederick Sanger , in 1949. Sanger correctly determined the amino acid sequence of insulin, thus conclusively demonstrating that proteins consisted of linear polymers of amino acids rather than branched chains, colloids , or cyclols . He won the Nobel Prize for this achievement in 1958. Christian Anfinsen 's studies of the oxidative folding process of ribonuclease A, for which he won

38025-581: Was not fully appreciated until 1926, when James B. Sumner showed that the enzyme urease was in fact a protein. Linus Pauling is credited with the successful prediction of regular protein secondary structures based on hydrogen bonding , an idea first put forth by William Astbury in 1933. Later work by Walter Kauzmann on denaturation , based partly on previous studies by Kaj Linderstrøm-Lang , contributed an understanding of protein folding and structure mediated by hydrophobic interactions . The first protein to have its amino acid chain sequenced

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