Neurotrophins are a family of proteins that induce the survival, development, and function of neurons .
87-508: They belong to a class of growth factors , secreted proteins that can signal particular cells to survive, differentiate, or grow. Growth factors such as neurotrophins that promote the survival of neurons are known as neurotrophic factors . Neurotrophic factors are secreted by target tissue and act by preventing the associated neuron from initiating programmed cell death – allowing the neurons to survive. Neurotrophins also induce differentiation of progenitor cells , to form neurons. Although
174-469: A myelinated axon , which are found periodically interspersed between segments of the myelin sheath. Therefore, at the point of the node of Ranvier, the axon is reduced in diameter. These nodes are areas where action potentials can be generated. In saltatory conduction , electrical currents produced at each node of Ranvier are conducted with little attenuation to the next node in line, where they remain strong enough to generate another action potential. Thus in
261-482: A myelinated axon, action potentials effectively "jump" from node to node, bypassing the myelinated stretches in between, resulting in a propagation speed much faster than even the fastest unmyelinated axon can sustain. An axon can divide into many branches called telodendria (Greek for 'end of tree'). At the end of each telodendron is an axon terminal (also called a terminal bouton or synaptic bouton, or end-foot ). Axon terminals contain synaptic vesicles that store
348-425: A nerve in the peripheral nervous system can be described as neurapraxia , axonotmesis , or neurotmesis . Concussion is considered a mild form of diffuse axonal injury . Axonal injury can also cause central chromatolysis . The dysfunction of axons in the nervous system is one of the major causes of many inherited and acquired neurological disorders that affect both peripheral and central neurons. When an axon
435-514: A neurite, causing it to elongate, will make it become an axon. Nonetheless, axonal development is achieved through a complex interplay between extracellular signaling, intracellular signaling and cytoskeletal dynamics. The extracellular signals that propagate through the extracellular matrix surrounding neurons play a prominent role in axonal development. These signaling molecules include proteins, neurotrophic factors , and extracellular matrix and adhesion molecules. Netrin (also known as UNC-6)
522-505: A neurite, converting it into an axon. As such, the overexpression of phosphatases that dephosphorylate PtdIns leads into the failure of polarization. The neurite with the lowest actin filament content will become the axon. PGMS concentration and f-actin content are inversely correlated; when PGMS becomes enriched at the tip of a neurite, its f-actin content is substantially decreased. In addition, exposure to actin-depolimerizing drugs and toxin B (which inactivates Rho-signaling ) causes
609-403: A presynaptic terminal, it activates the synaptic transmission process. The first step is rapid opening of calcium ion channels in the membrane of the axon, allowing calcium ions to flow inward across the membrane. The resulting increase in intracellular calcium concentration causes synaptic vesicles (tiny containers enclosed by a lipid membrane) filled with a neurotransmitter chemical to fuse with
696-554: A secreted protein, functions in axon formation. When the UNC-5 netrin receptor is mutated, several neurites are irregularly projected out of neurons and finally a single axon is extended anteriorly. The neurotrophic factors – nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NTF3) are also involved in axon development and bind to Trk receptors . The ganglioside -converting enzyme plasma membrane ganglioside sialidase (PMGS), which
783-453: A symmetrical crystal structure. There are two classes of receptors for neurotrophins: p75 and the "Trk" family of Tyrosine kinases receptors. Nerve growth factor (NGF), the prototypical growth factor , is a protein secreted by a neuron's target cell. NGF is critical for the survival and maintenance of sympathetic and sensory neurons. NGF is released from the target cells, binds to and activates its high affinity receptor TrkA on
870-564: Is nerve growth factor (NGF or beta-NGF), a vertebrate protein that stimulates division and differentiation of sympathetic and embryonic sensory neurons. NGF is mostly found outside the central nervous system (CNS), but slight traces have been detected in adult CNS tissues, although a physiological role for this is unknown. It has also been found in several snake venoms. In the peripheral and central neurons, neurotrophins are important regulators for survival, differentiation, and maintenance of nerve cells. They are small proteins that secrete into
957-445: Is a protein that has activity on certain neurons of the central nervous system and the peripheral nervous system; it helps to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses through axonal and dendritic sprouting. In the brain, it is active in the hippocampus , cortex , cerebellum , and basal forebrain – areas vital to learning, memory, and higher thinking. BDNF
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#17330852068171044-675: Is a secreted protein or a steroid hormone . Growth factors are important for regulating a variety of cellular processes. Growth factors typically act as signaling molecules between cells. Examples are cytokines and hormones that bind to specific receptors on the surface of their target cells . They often promote cell differentiation and maturation, which varies between growth factors. For example, epidermal growth factor (EGF) enhances osteogenic differentiation ( osteogenesis or bone formation), while fibroblast growth factors and vascular endothelial growth factors stimulate blood vessel differentiation ( angiogenesis ). Growth factor
1131-534: Is actually found in a range of tissue and cell types, not just the brain. Expression can be seen in the retina, the CNS, motor neurons, the kidneys, and the prostate. Exercise has been shown to increase the amount of BDNF and therefore serve as a vehicle for neuroplasticity. Neurotrophin-3, or NT-3, is a neurotrophic factor, in the NGF-family of neurotrophins. It is a protein growth factor that has activity on certain neurons of
1218-469: Is blocked and neutralized, it is possible to induce long-distance axonal regeneration which leads to enhancement of functional recovery in rats and mouse spinal cord. This has yet to be done on humans. A recent study has also found that macrophages activated through a specific inflammatory pathway activated by the Dectin-1 receptor are capable of promoting axon recovery, also however causing neurotoxicity in
1305-488: Is close to 1 millimeter in diameter, the size of a small pencil lead. The numbers of axonal telodendria (the branching structures at the end of the axon) can also differ from one nerve fiber to the next. Axons in the central nervous system (CNS) typically show multiple telodendria, with many synaptic end points. In comparison, the cerebellar granule cell axon is characterized by a single T-shaped branch node from which two parallel fibers extend. Elaborate branching allows for
1392-430: Is crushed, an active process of axonal degeneration takes place at the part of the axon furthest from the cell body. This degeneration takes place quickly following the injury, with the part of the axon being sealed off at the membranes and broken down by macrophages. This is known as Wallerian degeneration . Dying back of an axon can also take place in many neurodegenerative diseases , particularly when axonal transport
1479-475: Is dependent on the presence of neurotrophins. The expression of TrkB, which is found mainly in the CNS, does not cause apoptosis. This is thought to be because it is differentially located in the cell membrane while TrkA and TrkC are co-localized with p75NTR in lipid rafts . In the PNS (where NGF, NT-3 and NT-4 are mainly secreted) cell fate is determined by a single growth factor (i.e. neurotrophins). However, in
1566-403: Is distinct from somatic action potentials in three ways: 1. The signal has a shorter peak-trough duration (~150μs) than of pyramidal cells (~500μs) or interneurons (~250μs). 2. The voltage change is triphasic. 3. Activity recorded on a tetrode is seen on only one of the four recording wires. In recordings from freely moving rats, axonal signals have been isolated in white matter tracts including
1653-604: Is impaired, this is known as Wallerian-like degeneration. Studies suggest that the degeneration happens as a result of the axonal protein NMNAT2 , being prevented from reaching all of the axon. Demyelination of axons causes the multitude of neurological symptoms found in the disease multiple sclerosis . Dysmyelination is the abnormal formation of the myelin sheath. This is implicated in several leukodystrophies , and also in schizophrenia . A severe traumatic brain injury can result in widespread lesions to nerve tracts damaging
1740-507: Is involved in the activation of TrkA at the tip of neutrites, is required for the elongation of axons. PMGS asymmetrically distributes to the tip of the neurite that is destined to become the future axon. During axonal development, the activity of PI3K is increased at the tip of destined axon. Disrupting the activity of PI3K inhibits axonal development. Activation of PI3K results in the production of phosphatidylinositol (3,4,5)-trisphosphate (PtdIns) which can cause significant elongation of
1827-515: Is much more effective in the absence of Trk receptors due to the fact that activated Trk receptors suppress the JNK cascade. The expression of TrkA or TrkC receptors in the absence of neurotrophins can lead to apoptosis, but the mechanism is poorly understood. The addition of NGF (for TrkA) or NT-3 (for TrkC) prevents this apoptosis. For this reason TrkA and TrkC are referred to as dependence receptors , because whether they induce apoptosis or survival
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#17330852068171914-578: Is sometimes used interchangeably among scientists with the term cytokine . Historically, cytokines were associated with hematopoietic (blood and lymph forming) cells and immune system cells (e.g., lymphocytes and tissue cells from spleen , thymus , and lymph nodes ). For the circulatory system and bone marrow in which cells can occur in a liquid suspension and not bound up in solid tissue , it makes sense for them to communicate by soluble, circulating protein molecules . However, as different lines of research converged, it became clear that some of
2001-402: Is the corpus callosum that connects the two cerebral hemispheres , and this has around 20 million axons. The structure of a neuron is seen to consist of two separate functional regions, or compartments – the cell body together with the dendrites as one region, and the axonal region as the other. The axonal region or compartment, includes the axon hillock, the initial segment,
2088-411: Is the area formed from the cell body of the neuron as it extends to become the axon. It precedes the initial segment. The received action potentials that are summed in the neuron are transmitted to the axon hillock for the generation of an action potential from the initial segment. The axonal initial segment (AIS) is a structurally and functionally separate microdomain of the axon. One function of
2175-426: Is thought to carry a different cargo. The studies on transport in the axon led to the naming of kinesin. In the nervous system, axons may be myelinated , or unmyelinated. This is the provision of an insulating layer, called a myelin sheath. The myelin membrane is unique in its relatively high lipid to protein ratio. In the peripheral nervous system axons are myelinated by glial cells known as Schwann cells . In
2262-449: Is unmyelinated and contains a specialized complex of proteins. It is between approximately 20 and 60 μm in length and functions as the site of action potential initiation. Both the position on the axon and the length of the AIS can change showing a degree of plasticity that can fine-tune the neuronal output. A longer AIS is associated with a greater excitability. Plasticity is also seen in
2349-418: The guidance of neuronal axon growth. These cells that help axon guidance , are typically other neurons that are sometimes immature. When the axon has completed its growth at its connection to the target, the diameter of the axon can increase by up to five times, depending on the speed of conduction required. It has also been discovered through research that if the axons of a neuron were damaged, as long as
2436-462: The immunoglobulin superfamily. Another set of molecules called extracellular matrix - adhesion molecules also provide a sticky substrate for axons to grow along. Examples of these molecules include laminin , fibronectin , tenascin , and perlecan . Some of these are surface bound to cells and thus act as short range attractants or repellents. Others are difusible ligands and thus can have long range effects. Cells called guidepost cells assist in
2523-406: The nerve cell body . The function of the axon is to transmit information to different neurons, muscles, and glands. In certain sensory neurons ( pseudounipolar neurons ), such as those for touch and warmth, the axons are called afferent nerve fibers and the electrical impulse travels along these from the periphery to the cell body and from the cell body to the spinal cord along another branch of
2610-404: The neurotransmitter for release at the synapse . This makes multiple synaptic connections with other neurons possible. Sometimes the axon of a neuron may synapse onto dendrites of the same neuron, when it is known as an autapse . Some synaptic junctions appear along the length of an axon as it extends; these are called en passant boutons ("in passing boutons") and can be in the hundreds or even
2697-501: The nucleus , where it phosphorylates and transactivates c-Jun . The transactivation of c-Jun results in the transcription of pro-apoptotic factors TFF-a , Fas-L and Bak . The importance of sortilin in p75NTR-mediated apoptosis is exhibited by the fact that the inhibition of sortilin expression in neurons expressing p75NTR suppresses proNGF-mediated apoptosis, and the prevention of proBDNF binding to p75NTR and sortilin abolished apoptotic action. Activation of p75NTR-mediated apoptosis
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2784-672: The p75NTR . The PCD which occurs during brain development is responsible for the loss of a majority of neuroblasts and differentiating neurons. It is necessary because during development there is a massive over production of neurons which must be killed off to attain optimal function. In the development of both the peripheral nervous system (PNS) and the central nervous system (CNS) the p75NTR-neurotrophin binding activates multiple intracellular pathways which are important in regulating apoptosis. Proneurotrophins (proNTs) are neurotrophins which are released as biologically active uncleaved pro-peptides . Unlike mature neurotrophins which bind to
2871-922: The Aα, Aβ, and Aγ nerve fibers, respectively. Later findings by other researchers identified two groups of Aa fibers that were sensory fibers. These were then introduced into a system (Lloyd classification) that only included sensory fibers (though some of these were mixed nerves and were also motor fibers). This system refers to the sensory groups as Types and uses Roman numerals: Type Ia, Type Ib, Type II, Type III, and Type IV. Lower motor neurons have two kind of fibers: Different sensory receptors are innervated by different types of nerve fibers. Proprioceptors are innervated by type Ia, Ib and II sensory fibers, mechanoreceptors by type II and III sensory fibers and nociceptors and thermoreceptors by type III and IV sensory fibers. The autonomic nervous system has two kinds of peripheral fibers: In order of degree of severity, injury to
2958-428: The CNS (where BDNF is mainly secreted in the spinal cord , substantia nigra , amygdala , hypothalamus , cerebellum , hippocampus and cortex ) more factors determine cell fate, including neural activity and neurotransmitter input. Neurotrophins in the CNS have also been shown to play a more important role in neural cell differentiation and function rather than survival. For these reasons, compared to neurons in
3045-513: The CNS. The viability of these mice was moderate. The NT-4-knockout mice had moderate losses of their nodose petrosal ganglia and minor losses of their DRG, trigeminal ganglia and vestibular ganglia. The NT-4-knockout mice also had minor losses of facial motoneurons. These mice were very viable. The NT-3 knockout mice had losses of a majority of their DRG, trigeminal ganglia, cochlear ganglia and superior cervical ganglia and moderate losses of nodose petrosal ganglia and vestibular ganglia. In addition
3132-621: The NT-3-knockout mice had moderate losses of spinal moroneurons . These mice had very poor viability. These results show that the absence of different neurotrophins result in losses of different neuron populations (mainly in the PNS). Furthermore, the absence of the neurotrophin survival signal leads to apoptosis. Growth factors A growth factor is a naturally occurring substance capable of stimulating cell proliferation , wound healing , and occasionally cellular differentiation . Usually it
3219-487: The PNS, neurons of the CNS are less sensitive to the absence of a single neurotrophin or neurotrophin receptor during development; with the exception being neurons in the thalamus and substantia nigra . Gene knockout experiments were conducted to identify the neuronal populations in both the PNS and CNS that were affected by the loss of different neurotrophins during development and the extent to which these populations were affected. These knockout experiments resulted in
3306-587: The TrkA and p75 with high affinity (around 5 nM), and hence as so-called "microneurotrophins". DHEA has also been found to bind to the TrkB and TrkC, though while it activated the TrkC, it was unable to activate the TrkB. It has been proposed that DHEA may have been the ancestral ligand of the Trk receptors early on in the evolution of the nervous system , eventually being superseded by
3393-461: The ability of the AIS to change its distribution and to maintain the activity of neural circuitry at a constant level. The AIS is highly specialized for the fast conduction of nerve impulses . This is achieved by a high concentration of voltage-gated sodium channels in the initial segment where the action potential is initiated. The ion channels are accompanied by a high number of cell adhesion molecules and scaffold proteins that anchor them to
3480-399: The alveus and the corpus callosum as well hippocampal gray matter. In fact, the generation of action potentials in vivo is sequential in nature, and these sequential spikes constitute the digital codes in the neurons. Although previous studies indicate an axonal origin of a single spike evoked by short-term pulses, physiological signals in vivo trigger the initiation of sequential spikes at
3567-503: The axon length on the molecular level. These studies suggest that motor proteins carry signaling molecules from the soma to the growth cone and vice versa whose concentration oscillates in time with a length-dependent frequency. The axons of neurons in the human peripheral nervous system can be classified based on their physical features and signal conduction properties. Axons were known to have different thicknesses (from 0.1 to 20 μm) and these differences were thought to relate to
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3654-400: The axon sometimes consists of several regions that function more or less independently of each other. Axons are covered by a membrane known as an axolemma ; the cytoplasm of an axon is called axoplasm . Most axons branch, in some cases very profusely. The end branches of an axon are called telodendria . The swollen end of a telodendron is known as the axon terminal or end-foot which joins
3741-415: The axon to its target, is one of the six major stages in the overall development of the nervous system . Studies done on cultured hippocampal neurons suggest that neurons initially produce multiple neurites that are equivalent, yet only one of these neurites is destined to become the axon. It is unclear whether axon specification precedes axon elongation or vice versa, although recent evidence points to
3828-399: The axon's membrane and empty their contents into the extracellular space. The neurotransmitter is released from the presynaptic nerve through exocytosis . The neurotransmitter chemical then diffuses across to receptors located on the membrane of the target cell. The neurotransmitter binds to these receptors and activates them. Depending on the type of receptors that are activated, the effect on
3915-416: The axons in a condition known as diffuse axonal injury . This can lead to a persistent vegetative state . It has been shown in studies on the rat that axonal damage from a single mild traumatic brain injury, can leave a susceptibility to further damage, after repeated mild traumatic brain injuries. A nerve guidance conduit is an artificial means of guiding axon growth to enable neuroregeneration , and
4002-551: The brain and generate thousands of synaptic terminals. A bundle of axons make a nerve tract in the central nervous system , and a fascicle in the peripheral nervous system . In placental mammals the largest white matter tract in the brain is the corpus callosum , formed of some 200 million axons in the human brain . Axons are the primary transmission lines of the nervous system , and as bundles they form nerves . Some axons can extend up to one meter or more while others extend as little as one millimeter. The longest axons in
4089-409: The brain. The myelin gives the white appearance to the tissue in contrast to the grey matter of the cerebral cortex which contains the neuronal cell bodies. A similar arrangement is seen in the cerebellum . Bundles of myelinated axons make up the nerve tracts in the CNS. Where these tracts cross the midline of the brain to connect opposite regions they are called commissures . The largest of these
4176-443: The cell bodies of the neurons. In addition to propagating action potentials to axonal terminals, the axon is able to amplify the action potentials, which makes sure a secure propagation of sequential action potentials toward the axonal terminal. In terms of molecular mechanisms, voltage-gated sodium channels in the axons possess lower threshold and shorter refractory period in response to short-term pulses. The development of
4263-483: The cell body along the axon, carries mitochondria and membrane proteins needed for growth to the axon terminal. Ingoing retrograde transport carries cell waste materials from the axon terminal to the cell body. Outgoing and ingoing tracks use different sets of motor proteins . Outgoing transport is provided by kinesin , and ingoing return traffic is provided by dynein . Dynein is minus-end directed. There are many forms of kinesin and dynein motor proteins, and each
4350-594: The cell body and terminating at points where the axon makes synaptic contact with target cells. The defining characteristic of an action potential is that it is "all-or-nothing" – every action potential that an axon generates has essentially the same size and shape. This all-or-nothing characteristic allows action potentials to be transmitted from one end of a long axon to the other without any reduction in size. There are, however, some types of neurons with short axons that carry graded electrochemical signals, of variable amplitude. When an action potential reaches
4437-458: The central nervous system the myelin sheath is provided by another type of glial cell, the oligodendrocyte . Schwann cells myelinate a single axon. An oligodendrocyte can myelinate up to 50 axons. The composition of myelin is different in the two types. In the CNS the major myelin protein is proteolipid protein , and in the PNS it is myelin basic protein . Nodes of Ranvier (also known as myelin sheath gaps ) are short unmyelinated segments of
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#17330852068174524-418: The cytoskeleton. Interactions with ankyrin-G are important as it is the major organizer in the AIS. The axoplasm is the equivalent of cytoplasm in the cell. Microtubules form in the axoplasm at the axon hillock. They are arranged along the length of the axon, in overlapping sections, and all point in the same direction – towards the axon terminals. This is noted by the positive endings of
4611-412: The dendrite or cell body of another neuron forming a synaptic connection. Axons usually make contact with other neurons at junctions called synapses but can also make contact with muscle or gland cells. In some circumstances, the axon of one neuron may form a synapse with the dendrites of the same neuron, resulting in an autapse . At a synapse, the membrane of the axon closely adjoins the membrane of
4698-453: The development of the vertebrate nervous system, many neurons become redundant (because they have died, failed to connect to target cells, etc.) and are eliminated. At the same time, developing neurons send out axon outgrowths that contact their target cells. Such cells control their degree of innervation (the number of axon connections) by the secretion of various specific neurotrophic factors that are essential for neuron survival. One of these
4785-481: The entire process adheres to surfaces and explores the surrounding environment. Actin plays a major role in the mobility of this system. Environments with high levels of cell adhesion molecules (CAMs) create an ideal environment for axonal growth. This seems to provide a "sticky" surface for axons to grow along. Examples of CAMs specific to neural systems include N-CAM , TAG-1 – an axonal glycoprotein – and MAG , all of which are part of
4872-483: The fibers into three main groups using the letters A, B, and C. These groups, group A , group B , and group C include both the sensory fibers ( afferents ) and the motor fibers ( efferents ). The first group A, was subdivided into alpha, beta, gamma, and delta fibers – Aα, Aβ, Aγ, and Aδ. The motor neurons of the different motor fibers, were the lower motor neurons – alpha motor neuron , beta motor neuron , and gamma motor neuron having
4959-411: The formation of multiple axons. Consequently, the interruption of the actin network in a growth cone will promote its neurite to become the axon. Growing axons move through their environment via the growth cone , which is at the tip of the axon. The growth cone has a broad sheet-like extension called a lamellipodium which contain protrusions called filopodia . The filopodia are the mechanism by which
5046-433: The hallmark of traumatic brain injuries . Axonal damage is usually to the axon cytoskeleton disrupting transport. As a consequence protein accumulations such as amyloid-beta precursor protein can build up in a swelling resulting in a number of varicosities along the axon. Most axons carry signals in the form of action potentials, which are discrete electrochemical impulses that travel rapidly along an axon, starting at
5133-408: The human body are those of the sciatic nerve , which run from the base of the spinal cord to the big toe of each foot. The diameter of axons is also variable. Most individual axons are microscopic in diameter (typically about one micrometer (μm) across). The largest mammalian axons can reach a diameter of up to 20 μm. The squid giant axon , which is specialized to conduct signals very rapidly,
5220-403: The initial segment is to separate the main part of an axon from the rest of the neuron; another function is to help initiate action potentials. Both of these functions support neuron cell polarity , in which dendrites (and, in some cases the soma ) of a neuron receive input signals at the basal region, and at the apical region the neuron's axon provides output signals. The axon initial segment
5307-451: The integration of synaptic messages at the scale of the neuron. Extracellular recordings of action potential propagation in axons has been demonstrated in freely moving animals. While extracellular somatic action potentials have been used to study cellular activity in freely moving animals such as place cells , axonal activity in both white and gray matter can also be recorded. Extracellular recordings of axon action potential propagation
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#17330852068175394-451: The last two decades, growth factors have been increasingly used in the treatment of hematologic and oncologic diseases and cardiovascular diseases such as: Axon An axon (from Greek ἄξων áxōn , axis) or nerve fiber (or nerve fibre : see spelling differences ) is a long, slender projection of a nerve cell, or neuron , in vertebrates , that typically conducts electrical impulses known as action potentials away from
5481-433: The latter. If an axon that is not fully developed is cut, the polarity can change and other neurites can potentially become the axon. This alteration of polarity only occurs when the axon is cut at least 10 μm shorter than the other neurites. After the incision is made, the longest neurite will become the future axon and all the other neurites, including the original axon, will turn into dendrites. Imposing an external force on
5568-562: The loss of several neuron populations including the retina , cholinergic brainstem and the spinal cord . It was found that NGF-knockout mice had losses of a majority of their dorsal root ganglia (DRG), trigeminal ganglia and superior cervical ganglia . The viability of these mice was poor. The BDNF-knockout mice had losses of a majority of their vestibular ganglia and moderate losses of their DRG, trigeminal ganglia, nodose petrosal ganglia and cochlear ganglia. In addition they also had minor losses of their facial motoneurons located in
5655-419: The microtubules. This overlapping arrangement provides the routes for the transport of different materials from the cell body. Studies on the axoplasm has shown the movement of numerous vesicles of all sizes to be seen along cytoskeletal filaments – the microtubules, and neurofilaments , in both directions between the axon and its terminals and the cell body. Outgoing anterograde transport from
5742-439: The myelin sheath of a myelinated axon. Oligodendrocytes form the insulating myelin in the CNS. Along myelinated nerve fibers, gaps in the myelin sheath known as nodes of Ranvier occur at evenly spaced intervals. The myelination enables an especially rapid mode of electrical impulse propagation called saltatory conduction . The myelinated axons from the cortical neurons form the bulk of the neural tissue called white matter in
5829-447: The nervous system to help keep nerve cells alive. There are two distinct classes of glycosylated receptors that can bind to neurotrophins. These two proteins are p75 (NTR), which binds to all neurotrophins, and subtypes of Trk , which are each specific for different neurotrophins. The reported structure above is a 2.6 Å-resolution crystal structure of neurotrophin-3 (NT-3) complexed to the ectodomain of glycosylated p75 (NRT), forming
5916-410: The neuron, and is internalized into the responsive neuron. The NGF/TrkA complex is subsequently trafficked back to the neuron's cell body . This movement of NGF from axon tip to soma is thought to be involved in the long-distance signaling of neurons. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor found originally in the brain , but also found in the periphery. To be specific, it
6003-499: The neuron. Axons vary largely in length from a few micrometers up to meters in some animals. This emphasizes that there must be a cellular length regulation mechanism allowing the neurons both to sense the length of their axons and to control their growth accordingly. It was discovered that motor proteins play an important role in regulating the length of axons. Based on this observation, researchers developed an explicit model for axonal growth describing how motor proteins could affect
6090-502: The p75NTR with a low affinity, proNTs preferentially bind to the p75NTR with high affinity. The p75NTR contains a death domain on its cytoplasmic tail which when cleaved activates an apoptotic pathway. The binding of a proNT (proNGF or proBDNF) to p75NTR and its sortilin co-receptor (which binds the pro-domain of proNTs) causes a p75NTR-dependent signal transduction cascade. The cleaved death domain of p75NTR activates c-Jun N-terminal kinase (JNK). The activated JNK translocates into
6177-409: The peripheral and central nervous system ; it helps to support the survival and differentiation of existing neurons, and encourages the growth and differentiation of new neurons and synapses . NT-3 is the third neurotrophic factor to be characterized, after NGF and BDNF. NT-3 is unique among the neurotrophins in the number of neurons it has potential to stimulate, given its ability to activate two of
6264-453: The polypeptide neurotrophins. During neuron development neurotrophins play a key role in growth, differentiation , and survival. They also play an important role in the apoptotic programmed cell death (PCD) of neurons. Neurotrophic survival signals in neurons are mediated by the high-affinity binding of neurotrophins to their respective Trk receptor. In turn, a majority of neuronal apoptotic signals are mediated by neurotrophins binding to
6351-582: The receptor tyrosine kinase neurotrophin receptors ( TrkC and TrkB ). Mice born without the ability to make NT-3 have loss of proprioceptive and subsets of mechanoreceptive sensory neurons. Neurotrophin-4 (NT-4) is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase . It is also known as NT4, NT5, NTF4, and NT-4/5. The endogenous steroids dehydroepiandrosterone (DHEA) and its sulfate ester , DHEA sulfate (DHEA-S), have been identified as small-molecule agonists of
6438-477: The rest of the axon, and the axon telodendria, and axon terminals. It also includes the myelin sheath. The Nissl bodies that produce the neuronal proteins are absent in the axonal region. Proteins needed for the growth of the axon, and the removal of waste materials, need a framework for transport. This axonal transport is provided for in the axoplasm by arrangements of microtubules and type IV intermediate filaments known as neurofilaments . The axon hillock
6525-455: The same axon. Axon dysfunction can be the cause of many inherited and acquired neurological disorders that affect both the peripheral and central neurons . Nerve fibers are classed into three types – group A nerve fibers , group B nerve fibers , and group C nerve fibers . Groups A and B are myelinated , and group C are unmyelinated. These groups include both sensory fibers and motor fibers. Another classification groups only
6612-670: The same signaling proteins which the hematopoietic and immune systems use were also being used by all sorts of other cells and tissues, during development and in the mature organism. While growth factor implies a positive effect on cell proliferation , cytokine is a neutral term with respect to whether a molecule affects proliferation. While some cytokines can be growth factors, such as G-CSF and GM-CSF , others have an inhibitory effect on cell growth or cell proliferation. Some cytokines, such as Fas ligand , are used as "death" signals; they cause target cells to undergo programmed cell death or apoptosis . The nerve growth factor (NGF)
6699-761: The sensory fibers as Type I, Type II, Type III, and Type IV. An axon is one of two types of cytoplasmic protrusions from the cell body of a neuron; the other type is a dendrite . Axons are distinguished from dendrites by several features, including shape (dendrites often taper while axons usually maintain a constant radius), length (dendrites are restricted to a small region around the cell body while axons can be much longer), and function (dendrites receive signals whereas axons transmit them). Some types of neurons have no axon and transmit signals from their dendrites. In some species, axons can emanate from dendrites known as axon-carrying dendrites. No neuron ever has more than one axon; however in invertebrates such as insects or leeches
6786-404: The simultaneous transmission of messages to a large number of target neurons within a single region of the brain. There are two types of axons in the nervous system: myelinated and unmyelinated axons. Myelin is a layer of a fatty insulating substance, which is formed by two types of glial cells : Schwann cells and oligodendrocytes . In the peripheral nervous system Schwann cells form
6873-489: The soma (the cell body of a neuron) is not damaged, the axons would regenerate and remake the synaptic connections with neurons with the help of guidepost cells . This is also referred to as neuroregeneration . Nogo-A is a type of neurite outgrowth inhibitory component that is present in the central nervous system myelin membranes (found in an axon). It has a crucial role in restricting axonal regeneration in adult mammalian central nervous system. In recent studies, if Nogo-A
6960-475: The speed at which an action potential could travel along the axon – its conductance velocity . Erlanger and Gasser proved this hypothesis, and identified several types of nerve fiber, establishing a relationship between the diameter of an axon and its nerve conduction velocity. They published their findings in 1941 giving the first classification of axons. Axons are classified in two systems. The first one introduced by Erlanger and Gasser, grouped
7047-411: The target cell can be to excite the target cell, inhibit it, or alter its metabolism in some way. This entire sequence of events often takes place in less than a thousandth of a second. Afterward, inside the presynaptic terminal, a new set of vesicles is moved into position next to the membrane, ready to be released when the next action potential arrives. The action potential is the final electrical step in
7134-473: The target cell, and special molecular structures serve to transmit electrical or electrochemical signals across the gap. Some synaptic junctions appear along the length of an axon as it extends; these are called en passant boutons ("in passing boutons") and can be in the hundreds or even the thousands along one axon. Other synapses appear as terminals at the ends of axonal branches. A single axon, with all its branches taken together, can target multiple parts of
7221-611: The term neurotrophin may be used as a synonym for neurotrophic factor , but the term neurotrophin is more generally reserved for four structurally related factors: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). The term neurotrophic factor generally refers to these four neurotrophins, the GDNF family of ligands , and ciliary neurotrophic factor (CNTF), among other biomolecules . Neurotrophin-6 and neurotrophin-7 also exist, but are only found in zebrafish . During
7308-444: The thousands along one axon. In the normally developed brain, along the shaft of some axons are located pre-synaptic boutons also known as axonal varicosities and these have been found in regions of the hippocampus that function in the release of neurotransmitters. However, axonal varicosities are also present in neurodegenerative diseases where they interfere with the conduction of an action potential. Axonal varicosities are also
7395-477: The vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain (for example, the hippocampus ) retain the ability to grow new neurons from neural stem cells , a process known as neurogenesis . Neurotrophins are chemicals that help to stimulate and control neurogenesis. According to the United States National Library of Medicine 's medical subject headings ,
7482-565: Was first discovered by Rita Levi-Montalcini , which won her a Nobel Prize in Physiology or Medicine . Individual growth factor proteins tend to occur as members of larger families of structurally and evolutionarily related proteins. There are many families, some of which are listed below: The alpha granules in blood platelets contain growth factors PDGF, IGF-1, EGF, and TGF-β which begin healing of wounds by attracting and activating macrophages , fibroblasts , and endothelial cells . For
7569-414: Was the second neurotrophic factor to be characterized, after NGF and before neurotrophin-3. BDNF is one of the most active substances to stimulate neurogenesis. Mice born without the ability to make BDNF suffer developmental defects in the brain and sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal neural development . Despite its name, BDNF
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