Lernmatrix (German for "learning matrix") is a special type of artificial neural network (ANN) architecture, similar to associative memory , invented around 1960 by Karl Steinbuch , a pioneer in computer science and ANNs.
108-501: This model for learning systems could establish complex associations between certain sets of characteristics (e.g., letters of an alphabet) and their meanings. The Lernmatrix generally consists of n "characteristic lines" and m "meaning lines," where each characteristic line is connected to each meaning line, similar to how neurons in the brain are connected by synapses . (This can be realized in various ways – according to Steinbuch, this could be done by hardware or software). To train
216-442: A mesendodermal fate, with Oct4 actively suppressing genes associated with a neural ectodermal fate. Similarly, increased levels of Sox2 and decreased levels of Oct4 promote differentiation towards a neural ectodermal fate, with Sox2 inhibiting differentiation towards a mesendodermal fate. Regardless of the lineage cells differentiate down, suppression of NANOG has been identified as a necessary prerequisite for differentiation. In
324-455: A purine analog, has proven to induce dedifferentiation in myotubes . These manifestly dedifferentiated cells—now performing essentially as stem cells—could then redifferentiate into osteoblasts and adipocytes . Each specialized cell type in an organism expresses a subset of all the genes that constitute the genome of that species . Each cell type is defined by its particular pattern of regulated gene expression . Cell differentiation
432-501: A Lernmatrix, values are specified on the corresponding characteristic and meaning lines (binary or real); then the connections between all pairs of characteristic and meaning lines are strengthened by the Hebb rule . A trained Lernmatrix, when given a specific input on the characteristic lines, activates the corresponding meaning lines. In modern language, it is a linear projection module. By appropriately interconnecting several Lernmatrices,
540-457: A basophilic ("base-loving") dye. These structures consist of rough endoplasmic reticulum and associated ribosomal RNA . Named after German psychiatrist and neuropathologist Franz Nissl (1860–1919), they are involved in protein synthesis and their prominence can be explained by the fact that nerve cells are very metabolically active. Basophilic dyes such as aniline or (weakly) hematoxylin highlight negatively charged components, and so bind to
648-426: A bit less than 1/10 of a volt at baseline. This voltage has two functions: first, it provides a power source for an assortment of voltage-dependent protein machinery that is embedded in the membrane; second, it provides a basis for electrical signal transmission between different parts of the membrane. Numerous microscopic clumps called Nissl bodies (or Nissl substance) are seen when nerve cell bodies are stained with
756-658: A cell's size, shape, membrane potential , metabolic activity , and responsiveness to signals. These changes are largely due to highly controlled modifications in gene expression and are the study of epigenetics . With a few exceptions, cellular differentiation almost never involves a change in the DNA sequence itself. Metabolic composition, however, gets dramatically altered where stem cells are characterized by abundant metabolites with highly unsaturated structures whose levels decrease upon differentiation. Thus, different cells can have very different physical characteristics despite having
864-406: A conformational change in the receptor. The shape of the cytoplasmic domain of the receptor changes, and the receptor acquires enzymatic activity. The receptor then catalyzes reactions that phosphorylate other proteins, activating them. A cascade of phosphorylation reactions eventually activates a dormant transcription factor or cytoskeletal protein, thus contributing to the differentiation process in
972-544: A decrease in firing rate), or modulatory (causing long-lasting effects not directly related to firing rate). The two most common (90%+) neurotransmitters in the brain, glutamate and GABA , have largely consistent actions. Glutamate acts on several types of receptors and has effects that are excitatory at ionotropic receptors and a modulatory effect at metabotropic receptors . Similarly, GABA acts on several types of receptors, but all of them have inhibitory effects (in adult animals, at least). Because of this consistency, it
1080-461: A dendrite or an axon, particularly when the cell is undifferentiated . Most neurons receive signals via the dendrites and soma and send out signals down the axon. At the majority of synapses, signals cross from the axon of one neuron to the dendrite of another. However, synapses can connect an axon to another axon or a dendrite to another dendrite. The signaling process is partly electrical and partly chemical. Neurons are electrically excitable, due to
1188-430: A few closely related cell types. Finally, unipotent cells can differentiate into only one cell type, but are capable of self-renewal . In cytopathology , the level of cellular differentiation is used as a measure of cancer progression. " Grade " is a marker of how differentiated a cell in a tumor is. Three basic categories of cells make up the mammalian body: germ cells , somatic cells , and stem cells . Each of
SECTION 10
#17328017053741296-659: A hollow sphere of cells, called a blastocyst . The blastocyst has an outer layer of cells, and inside this hollow sphere, there is a cluster of cells called the inner cell mass . The cells of the inner cell mass go on to form virtually all of the tissues of the human body. Although the cells of the inner cell mass can form virtually every type of cell found in the human body, they cannot form an organism. These cells are referred to as pluripotent . Pluripotent stem cells undergo further specialization into multipotent progenitor cells that then give rise to functional cells. Examples of stem and progenitor cells include: A pathway that
1404-854: A large extent, differences in transcription factor binding are determined by the chromatin accessibility of their binding sites through histone modification and/or pioneer factors . In particular, it is important to know whether a nucleosome is covering a given genomic binding site or not. This can be determined using a chromatin immunoprecipitation assay. DNA-nucleosome interactions are characterized by two states: either tightly bound by nucleosomes and transcriptionally inactive, called heterochromatin , or loosely bound and usually, but not always, transcriptionally active, called euchromatin . The epigenetic processes of histone methylation and acetylation, and their inverses demethylation and deacetylation primarily account for these changes. The effects of acetylation and deacetylation are more predictable. An acetyl group
1512-748: A neuron leading to electrical activity, including pressure , stretch, chemical transmitters, and changes in the electric potential across the cell membrane. Stimuli cause specific ion-channels within the cell membrane to open, leading to a flow of ions through the cell membrane, changing the membrane potential. Neurons must maintain the specific electrical properties that define their neuron type. Thin neurons and axons require less metabolic expense to produce and carry action potentials, but thicker axons convey impulses more rapidly. To minimize metabolic expense while maintaining rapid conduction, many neurons have insulating sheaths of myelin around their axons. The sheaths are formed by glial cells: oligodendrocytes in
1620-465: A neuron responds at all, then it must respond completely. Greater intensity of stimulation, like brighter image/louder sound, does not produce a stronger signal but can increase firing frequency. Receptors respond in different ways to stimuli. Slowly adapting or tonic receptors respond to a steady stimulus and produce a steady rate of firing. Tonic receptors most often respond to increased stimulus intensity by increasing their firing frequency, usually as
1728-460: A neurotransmitter that binds to chemical receptors . The effect on the postsynaptic neuron is determined by the type of receptor that is activated, not by the presynaptic neuron or by the neurotransmitter. A neurotransmitter can be thought of as a key, and a receptor as a lock: the same neurotransmitter can activate multiple types of receptors. Receptors can be classified broadly as excitatory (causing an increase in firing rate), inhibitory (causing
1836-465: A power function of stimulus plotted against impulses per second. This can be likened to an intrinsic property of light where greater intensity of a specific frequency (color) requires more photons, as the photons can not become "stronger" for a specific frequency. Other receptor types include quickly adapting or phasic receptors, where firing decreases or stops with a steady stimulus; examples include skin which, when touched causes neurons to fire, but if
1944-432: A small number of genes, including OCT4 and NANOG, are methylated and their promoters repressed to prevent their further expression. Consistently, DNA methylation-deficient embryonic stem cells rapidly enter apoptosis upon in vitro differentiation. While the DNA sequence of most cells of an organism is the same, the binding patterns of transcription factors and the corresponding gene expression patterns are different. To
2052-451: A soft matrix without the use of diffusing factors. The stem-cell properties appear to be linked to tension in the cells' actin network. One identified mechanism for matrix-induced differentiation is tension-induced proteins, which remodel chromatin in response to mechanical stretch. The RhoA pathway is also implicated in this process. A billion-years-old, likely holozoan , protist , Bicellum brasieri with two types of cells, shows that
2160-548: A switching system can be built that, after completing certain training phases, is ultimately able to automatically determine the most probable associated meaning for an input sequence of features. Neurons A neuron , neurone , or nerve cell is an excitable cell that fires electric signals called action potentials across a neural network in the nervous system . Neurons communicate with other cells via synapses , which are specialized connections that commonly use minute amounts of chemical neurotransmitters to pass
2268-450: A technique called "double impregnation" and is still in use. In 1888 Ramón y Cajal published a paper about the bird cerebellum. In this paper, he stated that he could not find evidence for anastomosis between axons and dendrites and called each nervous element "an autonomous canton." This became known as the neuron doctrine , one of the central tenets of modern neuroscience . Cellular differentiation Cellular differentiation
SECTION 20
#17328017053742376-456: A universal classification of neurons that will apply to all neurons in the brain as well as across species. This is done by considering the three essential qualities of all neurons: electrophysiology, morphology, and the individual transcriptome of the cells. Besides being universal this classification has the advantage of being able to classify astrocytes as well. A method called patch-sequencing in which all three qualities can be measured at once
2484-847: Is Wnt signaling pathway . The Wnt pathway is involved in all stages of differentiation, and the ligand Wnt3a can substitute for the overexpression of c-Myc in the generation of induced pluripotent stem cells. On the other hand, disruption of β-catenin , a component of the Wnt signaling pathway, leads to decreased proliferation of neural progenitors. Growth factors comprise the second major set of candidates of epigenetic regulators of cellular differentiation. These morphogens are crucial for development, and include bone morphogenetic proteins , transforming growth factors (TGFs), and fibroblast growth factors (FGFs). TGFs and FGFs have been shown to sustain expression of OCT4, SOX2, and NANOG by downstream signaling to Smad proteins. Depletion of growth factors promotes
2592-447: Is a neurological disorder that results from the demyelination of axons in the central nervous system. Some neurons do not generate action potentials but instead generate a graded electrical signal , which in turn causes graded neurotransmitter release. Such non-spiking neurons tend to be sensory neurons or interneurons, because they cannot carry signals long distances. Neural coding is concerned with how sensory and other information
2700-625: Is a synapse in which a neuron's axon connects to its dendrites. The human brain has some 8.6 x 10 (eighty six billion) neurons. Each neuron has on average 7,000 synaptic connections to other neurons. It has been estimated that the brain of a three-year-old child has about 10 synapses (1 quadrillion). This number declines with age , stabilizing by adulthood. Estimates vary for an adult, ranging from 10 to 5 x 10 synapses (100 to 500 trillion). Beyond electrical and chemical signaling, studies suggest neurons in healthy human brains can also communicate through: They can also get modulated by input from
2808-401: Is associated with gene activation, whereas trimethylation of lysine 27 on histone 3 represses genes During differentiation, stem cells change their gene expression profiles. Recent studies have implicated a role for nucleosome positioning and histone modifications during this process. There are two components of this process: turning off the expression of embryonic stem cell (ESC) genes, and
2916-424: Is based on mechanical signalling by the cytoskeleton using Embryonic differentiation waves . The mechanical signal is then epigenetically transduced via signal transduction systems (of which specific molecules such as Wnt are part) to result in differential gene expression. In summary, the role of signaling in the epigenetic control of cell fate in mammals is largely unknown, but distinct examples exist that indicate
3024-417: Is called a neural circuit . A neuron contains all the structures of other cells such as a nucleus , mitochondria , and Golgi bodies but has additional unique structures such as an axon , and dendrites . The soma is a compact structure, and the axon and dendrites are filaments extruding from the soma. Dendrites typically branch profusely and extend a few hundred micrometers from the soma. The axon leaves
3132-419: Is common for neuroscientists to refer to cells that release glutamate as "excitatory neurons", and cells that release GABA as "inhibitory neurons". Some other types of neurons have consistent effects, for example, "excitatory" motor neurons in the spinal cord that release acetylcholine , and "inhibitory" spinal neurons that release glycine . The distinction between excitatory and inhibitory neurotransmitters
3240-555: Is either added to or removed from the positively charged Lysine residues in histones by enzymes called histone acetyltransferases or histone deactylases , respectively. The acetyl group prevents Lysine's association with the negatively charged DNA backbone. Methylation is not as straightforward, as neither methylation nor demethylation consistently correlate with either gene activation or repression. However, certain methylations have been repeatedly shown to either activate or repress genes. The trimethylation of lysine 4 on histone 3 (H3K4Me3)
3348-408: Is guided by the cell adhesion molecules consisting of four amino acids, arginine , glycine , asparagine , and serine , is created as the cellular blastomere differentiates from the single-layered blastula to the three primary layers of germ cells in mammals, namely the ectoderm , mesoderm and endoderm (listed from most distal (exterior) to proximal (interior)). The ectoderm ends up forming
Lernmatrix - Misplaced Pages Continue
3456-420: Is involved in the proliferation and self-renewal of stem cells. Finally, Sonic hedgehog , in addition to its role as a morphogen, promotes embryonic stem cell differentiation and the self-renewal of somatic stem cells. The problem, of course, is that the candidacy of these signaling pathways was inferred primarily on the basis of their role in development and cellular differentiation. While epigenetic regulation
3564-532: Is necessary for driving cellular differentiation, they are certainly not sufficient for this process. Direct modulation of gene expression through modification of transcription factors plays a key role that must be distinguished from heritable epigenetic changes that can persist even in the absence of the original environmental signals. Only a few examples of signaling pathways leading to epigenetic changes that alter cell fate currently exist, and we will focus on one of them. Expression of Shh (Sonic hedgehog) upregulates
3672-478: Is not absolute. Rather, it depends on the class of chemical receptors present on the postsynaptic neuron. In principle, a single neuron, releasing a single neurotransmitter, can have excitatory effects on some targets, inhibitory effects on others, and modulatory effects on others still. For example, photoreceptor cells in the retina constantly release the neurotransmitter glutamate in the absence of light. So-called OFF bipolar cells are, like most neurons, excited by
3780-417: Is often controlled by cell signaling . Many of the signal molecules that convey information from cell to cell during the control of cellular differentiation are called growth factors . Although the details of specific signal transduction pathways vary, these pathways often share the following general steps. A ligand produced by one cell binds to a receptor in the extracellular region of another cell, inducing
3888-459: Is represented in the brain by neurons. The main goal of studying neural coding is to characterize the relationship between the stimulus and the individual or ensemble neuronal responses and the relationships among the electrical activities of the neurons within the ensemble. It is thought that neurons can encode both digital and analog information. The conduction of nerve impulses is an example of an all-or-none response. In other words, if
3996-545: Is termed a "bivalent domain" and rendering these genes sensitive to rapid induction or repression. Regulation of gene expression is further achieved through DNA methylation, in which the DNA methyltransferase -mediated methylation of cytosine residues in CpG dinucleotides maintains heritable repression by controlling DNA accessibility. The majority of CpG sites in embryonic stem cells are unmethylated and appear to be associated with H3K4me3-carrying nucleosomes. Upon differentiation,
4104-463: Is the extent and complexity of the role of epigenetic processes in the determination of cell fate. A clear answer to this question can be seen in the 2011 paper by Lister R, et al. on aberrant epigenomic programming in human induced pluripotent stem cells . As induced pluripotent stem cells (iPSCs) are thought to mimic embryonic stem cells in their pluripotent properties, few epigenetic differences should exist between them. To test this prediction,
4212-589: Is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular organism as it changes from a simple zygote to a complex system of tissues and cell types. Differentiation continues in adulthood as adult stem cells divide and create fully differentiated daughter cells during tissue repair and during normal cell turnover. Some differentiation occurs in response to antigen exposure. Differentiation dramatically changes
4320-461: Is thus a transition of a cell from one cell type to another and it involves a switch from one pattern of gene expression to another. Cellular differentiation during development can be understood as the result of a gene regulatory network . A regulatory gene and its cis-regulatory modules are nodes in a gene regulatory network; they receive input and create output elsewhere in the network. The systems biology approach to developmental biology emphasizes
4428-432: Is transferred to the axon, which fires. If the pressure is steady, the stimulus ends; thus, these neurons typically respond with a transient depolarization during the initial deformation and again when the pressure is removed, which causes the corpuscle to change shape again. Other types of adaptation are important in extending the function of several other neurons. The German anatomist Heinrich Wilhelm Waldeyer introduced
Lernmatrix - Misplaced Pages Continue
4536-643: Is used extensively by the Allen Institute for Brain Science . In 2023, a comprehensive cell atlas of the adult, and developing human brain at the transcriptional, epigenetic, and functional levels was created through an international collaboration of researchers using the most cutting-edge molecular biology approaches. Neurons communicate with each other via synapses , where either the axon terminal of one cell contacts another neuron's dendrite, soma, or, less commonly, axon. Neurons such as Purkinje cells in
4644-425: Is usually about 10–25 micrometers in diameter and often is not much larger than the cell nucleus it contains. The longest axon of a human motor neuron can be over a meter long, reaching from the base of the spine to the toes. Sensory neurons can have axons that run from the toes to the posterior column of the spinal cord, over 1.5 meters in adults. Giraffes have single axons several meters in length running along
4752-409: The brain and spinal cord , and the peripheral nervous system , which includes the autonomic , enteric and somatic nervous systems . In vertebrates, the majority of neurons belong to the central nervous system , but some reside in peripheral ganglia , and many sensory neurons are situated in sensory organs such as the retina and cochlea . Axons may bundle into nerve fascicles that make up
4860-484: The epigenome , and the majority of current knowledge about the subject consists of speculations on plausible candidate regulators of epigenetic remodeling. We will first discuss several major candidates thought to be involved in the induction and maintenance of both embryonic stem cells and their differentiated progeny, and then turn to one example of specific signaling pathways in which more direct evidence exists for its role in epigenetic change. The first major candidate
4968-431: The nerves in the peripheral nervous system (like strands of wire that make up a cable). In the central nervous system bundles of axons are called nerve tracts . Neurons are highly specialized for the processing and transmission of cellular signals. Given the diversity of functions performed in different parts of the nervous system, there is a wide variety in their shape, size, and electrochemical properties. For instance,
5076-446: The peptidergic secretory cells. They eventually gained new gene modules which enabled cells to create post-synaptic scaffolds and ion channels that generate fast electrical signals. The ability to generate electric signals was a key innovation in the evolution of the nervous system. Neurons are typically classified into three types based on their function. Sensory neurons respond to stimuli such as touch, sound, or light that affect
5184-686: The squid giant axon could be used to study neuronal electrical properties. It is larger than but similar to human neurons, making it easier to study. By inserting electrodes into the squid giant axons, accurate measurements were made of the membrane potential . The cell membrane of the axon and soma contain voltage-gated ion channels that allow the neuron to generate and propagate an electrical signal (an action potential). Some neurons also generate subthreshold membrane potential oscillations . These signals are generated and propagated by charge-carrying ions including sodium (Na ), potassium (K ), chloride (Cl ), and calcium (Ca ) . Several stimuli can activate
5292-409: The tubulin of microtubules . Class III β-tubulin is found almost exclusively in neurons. Actin is predominately found at the tips of axons and dendrites during neuronal development. There the actin dynamics can be modulated via an interplay with microtubule. There are different internal structural characteristics between axons and dendrites. Typical axons seldom contain ribosomes , except some in
5400-443: The activation of cell fate genes. Lysine specific demethylase 1 ( KDM1A ) is thought to prevent the use of enhancer regions of pluripotency genes, thereby inhibiting their transcription. It interacts with Mi-2/NuRD complex (nucleosome remodelling and histone deacetylase) complex, giving an instance where methylation and acetylation are not discrete and mutually exclusive, but intertwined processes. A final question to ask concerns
5508-560: The approximately 37.2 trillion (3.72x10 ) cells in an adult human has its own copy or copies of the genome except certain cell types , such as red blood cells , that lack nuclei in their fully differentiated state. Most cells are diploid ; they have two copies of each chromosome . Such cells, called somatic cells, make up most of the human body, such as skin and muscle cells. Cells differentiate to specialize for different functions. Germ line cells are any line of cells that give rise to gametes —eggs and sperm—and thus are continuous through
SECTION 50
#17328017053745616-688: The authors conducted whole-genome profiling of DNA methylation patterns in several human embryonic stem cell (ESC), iPSC, and progenitor cell lines. Female adipose cells, lung fibroblasts , and foreskin fibroblasts were reprogrammed into induced pluripotent state with the OCT4 , SOX2 , KLF4 , and MYC genes. Patterns of DNA methylation in ESCs, iPSCs, somatic cells were compared. Lister R, et al. observed significant resemblance in methylation levels between embryonic and induced pluripotent cells. Around 80% of CG dinucleotides in ESCs and iPSCs were methylated,
5724-417: The authors discovered 1175 regions of differential CG dinucleotide methylation between at least one ES or iPS cell line. By comparing these regions of differential methylation with regions of cytosine methylation in the original somatic cells, 44-49% of differentially methylated regions reflected methylation patterns of the respective progenitor somatic cells, while 51-56% of these regions were dissimilar to both
5832-584: The axon terminal, it opens voltage-gated calcium channels , allowing calcium ions to enter the terminal. Calcium causes synaptic vesicles filled with neurotransmitter molecules to fuse with the membrane, releasing their contents into the synaptic cleft. The neurotransmitters diffuse across the synaptic cleft and activate receptors on the postsynaptic neuron. High cytosolic calcium in the axon terminal triggers mitochondrial calcium uptake, which, in turn, activates mitochondrial energy metabolism to produce ATP to support continuous neurotransmission. An autapse
5940-488: The cell to pull against the matrix at focal adhesions, which triggers a cellular mechano-transducer to generate a signal to be informed what force is needed to deform the matrix. To determine the key players in matrix-elasticity-driven lineage specification in MSCs, different matrix microenvironments were mimicked. From these experiments, it was concluded that focal adhesions of the MSCs were the cellular mechano-transducer sensing
6048-485: The cell's final function (e.g. myosin and actin for a muscle cell). Differentiation may continue to occur after terminal differentiation if the capacity and functions of the cell undergo further changes. Among dividing cells, there are multiple levels of cell potency , which is the cell's ability to differentiate into other cell types. A greater potency indicates a larger number of cell types that can be derived. A cell that can differentiate into all cell types, including
6156-399: The cells of the sensory organs , and they send signals to the spinal cord or brain . Motor neurons receive signals from the brain and spinal cord to control everything from muscle contractions to glandular output . Interneurons connect neurons to other neurons within the same region of the brain or spinal cord. When multiple neurons are functionally connected together, they form what
6264-411: The cellular mechanisms underlying these switches, in animal species these are very different from the well-characterized gene regulatory mechanisms of bacteria , and even from those of the animals' closest unicellular relatives . Specifically, cell differentiation in animals is highly dependent on biomolecular condensates of regulatory proteins and enhancer DNA sequences. Cellular differentiation
6372-438: The central nervous system and Schwann cells in the peripheral nervous system. The sheath enables action potentials to travel faster than in unmyelinated axons of the same diameter, whilst using less energy. The myelin sheath in peripheral nerves normally runs along the axon in sections about 1 mm long, punctuated by unsheathed nodes of Ranvier , which contain a high density of voltage-gated ion channels. Multiple sclerosis
6480-548: The cerebellum can have over 1000 dendritic branches, making connections with tens of thousands of other cells; other neurons, such as the magnocellular neurons of the supraoptic nucleus , have only one or two dendrites, each of which receives thousands of synapses. Synapses can be excitatory or inhibitory, either increasing or decreasing activity in the target neuron, respectively. Some neurons also communicate via electrical synapses, which are direct, electrically conductive junctions between cells. When an action potential reaches
6588-434: The decision to adopt a stem, progenitor, or mature cell fate This section will focus primarily on mammalian stem cells . In systems biology and mathematical modeling of gene regulatory networks, cell-fate determination is predicted to exhibit certain dynamics, such as attractor-convergence (the attractor can be an equilibrium point, limit cycle or strange attractor ) or oscillatory. The first question that can be asked
SECTION 60
#17328017053746696-761: The differences of the matrix elasticity. The non-muscle myosin IIa-c isoforms generates the forces in the cell that lead to signaling of early commitment markers. Nonmuscle myosin IIa generates the least force increasing to non-muscle myosin IIc. There are also factors in the cell that inhibit non-muscle myosin II, such as blebbistatin . This makes the cell effectively blind to the surrounding matrix. Researchers have achieved some success in inducing stem cell-like properties in HEK 239 cells by providing
6804-554: The differentiated phenotype. Simultaneously, differentiation and development-promoting genes are activated by Trithorax group (TrxG) chromatin regulators and lose their repression. TrxG proteins are recruited at regions of high transcriptional activity, where they catalyze the trimethylation of histone H3 lysine 4 ( H3K4me3 ) and promote gene activation through histone acetylation. PcG and TrxG complexes engage in direct competition and are thought to be functionally antagonistic, creating at differentiation and development-promoting loci what
6912-648: The differentiation of ESCs, while genes with bivalent chromatin can become either more restrictive or permissive in their transcription. Several other signaling pathways are also considered to be primary candidates. Cytokine leukemia inhibitory factors are associated with the maintenance of mouse ESCs in an undifferentiated state. This is achieved through its activation of the Jak-STAT3 pathway, which has been shown to be necessary and sufficient towards maintaining mouse ESC pluripotency. Retinoic acid can induce differentiation of human and mouse ESCs, and Notch signaling
7020-490: The electric signal from the presynaptic neuron to the target cell through the synaptic gap. Neurons are the main components of nervous tissue in all animals except sponges and placozoans . Plants and fungi do not have nerve cells. Molecular evidence suggests that the ability to generate electric signals first appeared in evolution some 700 to 800 million years ago, during the Tonian period. Predecessors of neurons were
7128-400: The entire length of their necks. Much of what is known about axonal function comes from studying the squid giant axon , an ideal experimental preparation because of its relatively immense size (0.5–1 millimeter thick, several centimeters long). Fully differentiated neurons are permanently postmitotic however, stem cells present in the adult brain may regenerate functional neurons throughout
7236-551: The environment and hormones released from other parts of the organism, which could be influenced more or less directly by neurons. This also applies to neurotrophins such as BDNF . The gut microbiome is also connected with the brain. Neurons also communicate with microglia , the brain's main immune cells via specialized contact sites, called "somatic junctions". These connections enable microglia to constantly monitor and regulate neuronal functions, and exert neuroprotection when needed. In 1937 John Zachary Young suggested that
7344-477: The excitation from the OFF bipolar cells, silencing them. It is possible to identify the type of inhibitory effect a presynaptic neuron will have on a postsynaptic neuron, based on the proteins the presynaptic neuron expresses. Parvalbumin -expressing neurons typically dampen the output signal of the postsynaptic neuron in the visual cortex , whereas somatostatin -expressing neurons typically block dendritic inputs to
7452-401: The first two of which are used in induced pluripotent stem cell (iPSC) reprogramming, along with Klf4 and c-Myc – are highly expressed in undifferentiated embryonic stem cells and are necessary for the maintenance of their pluripotency . It is thought that they achieve this through alterations in chromatin structure, such as histone modification and DNA methylation, to restrict or permit
7560-641: The former mechanism, distinct daughter cells are created during cytokinesis because of an uneven distribution of regulatory molecules in the parent cell; the distinct cytoplasm that each daughter cell inherits results in a distinct pattern of differentiation for each daughter cell. A well-studied example of pattern formation by asymmetric divisions is body axis patterning in Drosophila . RNA molecules are an important type of intracellular differentiation control signal. The molecular and genetic basis of asymmetric cell divisions has also been studied in green algae of
7668-557: The generations. Stem cells, on the other hand, have the ability to divide for indefinite periods and to give rise to specialized cells. They are best described in the context of normal human development. Development begins when a sperm fertilizes an egg and creates a single cell that has the potential to form an entire organism. In the first hours after fertilization, this cell divides into identical cells. In humans, approximately four days after fertilization and after several cycles of cell division, these cells begin to specialize, forming
7776-453: The genus Volvox , a model system for studying how unicellular organisms can evolve into multicellular organisms. In Volvox carteri , the 16 cells in the anterior hemisphere of a 32-cell embryo divide asymmetrically, each producing one large and one small daughter cell. The size of the cell at the end of all cell divisions determines whether it becomes a specialized germ or somatic cell. Since each cell, regardless of cell type, possesses
7884-484: The importance of investigating how developmental mechanisms interact to produce predictable patterns ( morphogenesis ). However, an alternative view has been proposed recently . Based on stochastic gene expression, cellular differentiation is the result of a Darwinian selective process occurring among cells. In this frame, protein and gene networks are the result of cellular processes and not their cause. While evolutionarily conserved molecular processes are involved in
7992-486: The initial segment. Dendrites contain granular endoplasmic reticulum or ribosomes, in diminishing amounts as the distance from the cell body increases. Neurons vary in shape and size and can be classified by their morphology and function. The anatomist Camillo Golgi grouped neurons into two types; type I with long axons used to move signals over long distances and type II with short axons, which can often be confused with dendrites. Type I cells can be further classified by
8100-408: The laboratory, cells can change shape or may lose specific properties such as protein expression—which processes are also termed dedifferentiation. Some hypothesize that dedifferentiation is an aberration that likely results in cancers , but others explain it as a natural part of the immune response that was lost to humans at some point of evolution. A newly discovered molecule dubbed reversine ,
8208-471: The lens vesicle of surface fish can induce other parts of the eye to develop in cave- and surface-dwelling fish, while the lens vesicle of the cave-dwelling fish cannot. Other important mechanisms fall under the category of asymmetric cell divisions , divisions that give rise to daughter cells with distinct developmental fates. Asymmetric cell divisions can occur because of asymmetrically expressed maternal cytoplasmic determinants or because of signaling. In
8316-457: The life of an organism (see neurogenesis ). Astrocytes are star-shaped glial cells that have been observed to turn into neurons by virtue of their stem cell-like characteristic of pluripotency . Like all animal cells, the cell body of every neuron is enclosed by a plasma membrane , a bilayer of lipid molecules with many types of protein structures embedded in it. A lipid bilayer is a powerful electrical insulator , but in neurons, many of
8424-410: The likely existence of further such mechanisms. In order to fulfill the purpose of regenerating a variety of tissues, adult stems are known to migrate from their niches, adhere to new extracellular matrices (ECM) and differentiate. The ductility of these microenvironments are unique to different tissue types. The ECM surrounding brain, muscle and bone tissues range from soft to stiff. The transduction of
8532-411: The location of the soma. The basic morphology of type I neurons, represented by spinal motor neurons , consists of a cell body called the soma and a long thin axon covered by a myelin sheath . The dendritic tree wraps around the cell body and receives signals from other neurons. The end of the axon has branching axon terminals that release neurotransmitters into a gap called the synaptic cleft between
8640-408: The maintenance of voltage gradients across their membranes . If the voltage changes by a large enough amount over a short interval, the neuron generates an all-or-nothing electrochemical pulse called an action potential . This potential travels rapidly along the axon and activates synaptic connections as it reaches them. Synaptic signals may be excitatory or inhibitory , increasing or reducing
8748-429: The mechanisms of reprogramming (and by extension, differentiation) are very complex and cannot be easily duplicated, as seen by the significant number of differentially methylated regions between ES and iPS cell lines. Now that these two points have been established, we can examine some of the epigenetic mechanisms that are thought to regulate cellular differentiation. Three transcription factors, OCT4, SOX2, and NANOG –
8856-434: The net voltage that reaches the soma. In most cases, neurons are generated by neural stem cells during brain development and childhood. Neurogenesis largely ceases during adulthood in most areas of the brain. Neurons are the primary components of the nervous system , along with the glial cells that give them structural and metabolic support. The nervous system is made up of the central nervous system , which includes
8964-406: The object maintains even pressure, the neurons stop firing. The neurons of the skin and muscles that are responsive to pressure and vibration have filtering accessory structures that aid their function. The pacinian corpuscle is one such structure. It has concentric layers like an onion, which form around the axon terminal. When pressure is applied and the corpuscle is deformed, mechanical stimulus
9072-564: The phosphate backbone of the ribosomal RNA. The cell body of a neuron is supported by a complex mesh of structural proteins called neurofilaments , which together with neurotubules (neuronal microtubules) are assembled into larger neurofibrils. Some neurons also contain pigment granules, such as neuromelanin (a brownish-black pigment that is byproduct of synthesis of catecholamines ), and lipofuscin (a yellowish-brown pigment), both of which accumulate with age. Other structural proteins that are important for neuronal function are actin and
9180-448: The placental tissue, is known as totipotent . In mammals, only the zygote and subsequent blastomeres are totipotent, while in plants, many differentiated cells can become totipotent with simple laboratory techniques. A cell that can differentiate into all cell types of the adult organism is known as pluripotent . Such cells are called meristematic cells in higher plants and embryonic stem cells in animals, though some groups report
9288-467: The postsynaptic neuron. Neurons have intrinsic electroresponsive properties like intrinsic transmembrane voltage oscillatory patterns. So neurons can be classified according to their electrophysiological characteristics: Neurotransmitters are chemical messengers passed from one neuron to another neuron or to a muscle cell or gland cell . Since 2012 there has been a push from the cellular and computational neuroscience community to come up with
9396-431: The presence of adult pluripotent cells. Virally induced expression of four transcription factors Oct4 , Sox2 , c-Myc , and Klf4 ( Yamanaka factors ) is sufficient to create pluripotent (iPS) cells from adult fibroblasts . A multipotent cell is one that can differentiate into multiple different, but closely related cell types. Oligopotent cells are more restricted than multipotent, but can still differentiate into
9504-617: The production of BMI1 , a component of the PcG complex that recognizes H3K27me3 . This occurs in a Gli-dependent manner, as Gli1 and Gli2 are downstream effectors of the Hedgehog signaling pathway . In culture, Bmi1 mediates the Hedgehog pathway's ability to promote human mammary stem cell self-renewal. In both humans and mice, researchers showed Bmi1 to be highly expressed in proliferating immature cerebellar granule cell precursors. When Bmi1
9612-514: The progenitor and embryonic cell lines. In vitro -induced differentiation of iPSC lines saw transmission of 88% and 46% of hyper and hypo-methylated differentially methylated regions, respectively. Two conclusions are readily apparent from this study. First, epigenetic processes are heavily involved in cell fate determination , as seen from the similar levels of cytosine methylation between induced pluripotent and embryonic stem cells, consistent with their respective patterns of transcription . Second,
9720-434: The protein structures embedded in the membrane are electrically active. These include ion channels that permit electrically charged ions to flow across the membrane and ion pumps that chemically transport ions from one side of the membrane to the other. Most ion channels are permeable only to specific types of ions. Some ion channels are voltage gated , meaning that they can be switched between open and closed states by altering
9828-653: The realm of gene silencing , Polycomb repressive complex 2 , one of two classes of the Polycomb group (PcG) family of proteins, catalyzes the di- and tri-methylation of histone H3 lysine 27 (H3K27me2/me3). By binding to the H3K27me2/3-tagged nucleosome, PRC1 (also a complex of PcG family proteins) catalyzes the mono-ubiquitinylation of histone H2A at lysine 119 (H2AK119Ub1), blocking RNA polymerase II activity and resulting in transcriptional suppression. PcG knockout ES cells do not differentiate efficiently into
9936-474: The released glutamate. However, neighboring target neurons called ON bipolar cells are instead inhibited by glutamate, because they lack typical ionotropic glutamate receptors and instead express a class of inhibitory metabotropic glutamate receptors. When light is present, the photoreceptors cease releasing glutamate, which relieves the ON bipolar cells from inhibition, activating them; this simultaneously removes
10044-416: The role of cell signaling in influencing the epigenetic processes governing differentiation. Such a role should exist, as it would be reasonable to think that extrinsic signaling can lead to epigenetic remodeling, just as it can lead to changes in gene expression through the activation or repression of different transcription factors. Little direct data is available concerning the specific signals that influence
10152-419: The same genome . A specialized type of differentiation, known as terminal differentiation , is of importance in some tissues, including vertebrate nervous system , striated muscle , epidermis and gut. During terminal differentiation, a precursor cell formerly capable of cell division permanently leaves the cell cycle, dismantles the cell cycle machinery and often expresses a range of genes characteristic of
10260-419: The same genome, determination of cell type must occur at the level of gene expression. While the regulation of gene expression can occur through cis- and trans-regulatory elements including a gene's promoter and enhancers , the problem arises as to how this expression pattern is maintained over numerous generations of cell division . As it turns out, epigenetic processes play a crucial role in regulating
10368-511: The same was true of only 60% of CG dinucleotides in somatic cells. In addition, somatic cells possessed minimal levels of cytosine methylation in non-CG dinucleotides, while induced pluripotent cells possessed similar levels of methylation as embryonic stem cells, between 0.5 and 1.5%. Thus, consistent with their respective transcriptional activities, DNA methylation patterns, at least on the genomic level, are similar between ESCs and iPSCs. However, upon examining methylation patterns more closely,
10476-512: The silver staining technique used to visualize nervous tissue under light microscopy. The neuron's place as the primary functional unit of the nervous system was first recognized in the late 19th century through the work of the Spanish anatomist Santiago Ramón y Cajal . To make the structure of individual neurons visible, Ramón y Cajal improved a silver staining process that had been developed by Camillo Golgi . The improved process involves
10584-465: The skin and the nervous system, the mesoderm forms the bones and muscular tissue, and the endoderm forms the internal organ tissues. Dedifferentiation , or integration, is a cellular process seen in the more basal life forms in animals, such as worms and amphibians where a differentiated cell reverts to an earlier developmental stage—usually as part of a regenerative process. Dedifferentiation also occurs in plant cells. And, in cell culture in
10692-406: The soma at a swelling called the axon hillock and travels for as far as 1 meter in humans or more in other species. It branches but usually maintains a constant diameter. At the farthest tip of the axon's branches are axon terminals , where the neuron can transmit a signal across the synapse to another cell. Neurons may lack dendrites or have no axons. The term neurite is used to describe either
10800-435: The soma of a neuron can vary from 4 to 100 micrometers in diameter. The accepted view of the neuron attributes dedicated functions to its various anatomical components; however, dendrites and axons often act in ways contrary to their so-called main function. Axons and dendrites in the central nervous system are typically only about one micrometer thick, while some in the peripheral nervous system are much thicker. The soma
10908-419: The stem cells into these cells types is not directed solely by chemokine cues and cell to cell signaling. The elasticity of the microenvironment can also affect the differentiation of mesenchymal stem cells (MSCs which originate in bone marrow.) When MSCs are placed on substrates of the same stiffness as brain, muscle and bone ECM, the MSCs take on properties of those respective cell types. Matrix sensing requires
11016-478: The target cell. Cells and tissues can vary in competence, their ability to respond to external signals. Signal induction refers to cascades of signaling events, during which a cell or tissue signals to another cell or tissue to influence its developmental fate. Yamamoto and Jeffery investigated the role of the lens in eye formation in cave- and surface-dwelling fish, a striking example of induction. Through reciprocal transplants, Yamamoto and Jeffery found that
11124-695: The term neuron in 1891, based on the ancient Greek νεῦρον neuron 'sinew, cord, nerve'. The word was adopted in French with the spelling neurone . That spelling was also used by many writers in English, but has now become rare in American usage and uncommon in British usage. Some previous works used nerve cell ( cellule nervose ), as adopted in Camillo Golgi 's 1873 paper on the discovery of
11232-422: The terminals and the dendrites of the next neuron. Most neurons can be anatomically characterized as: Some unique neuronal types can be identified according to their location in the nervous system and distinct shape. Some examples are: Afferent and efferent also refer generally to neurons that, respectively, bring information to or send information from the brain. A neuron affects other neurons by releasing
11340-532: The three germ layers, and deletion of the PRC1 and PRC2 genes leads to increased expression of lineage-affiliated genes and unscheduled differentiation. Presumably, PcG complexes are responsible for transcriptionally repressing differentiation and development-promoting genes. Alternately, upon receiving differentiation signals, PcG proteins are recruited to promoters of pluripotency transcription factors. PcG-deficient ES cells can begin differentiation but cannot maintain
11448-419: The transcription of target genes. While highly expressed, their levels require a precise balance to maintain pluripotency, perturbation of which will promote differentiation towards different lineages based on how the gene expression levels change. Differential regulation of Oct-4 and SOX2 levels have been shown to precede germ layer fate selection. Increased levels of Oct4 and decreased levels of Sox2 promote
11556-404: The voltage difference across the membrane. Others are chemically gated, meaning that they can be switched between open and closed states by interactions with chemicals that diffuse through the extracellular fluid. The ion materials include sodium , potassium , chloride , and calcium . The interactions between ion channels and ion pumps produce a voltage difference across the membrane, typically
11664-478: Was knocked out in mice, impaired cerebellar development resulted, leading to significant reductions in postnatal brain mass along with abnormalities in motor control and behavior. A separate study showed a significant decrease in neural stem cell proliferation along with increased astrocyte proliferation in Bmi null mice. An alternative model of cellular differentiation during embryogenesis is that positional information
#373626