| Neurotrophin | |||||||||
|---|---|---|---|---|---|---|---|---|---|
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| Identifiers | |||||||||
| Symbol | NGF | ||||||||
| Pfam | PF00243 | ||||||||
| InterPro | IPR002072 | ||||||||
| PROSITE | PDOC00221 | ||||||||
| SCOP2 | 1bet /SCOPe /SUPFAM | ||||||||
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Neurotrophins are a family ofproteins that induce the survival,[1] development, and function[2] ofneurons.
They belong to a class ofgrowth factors. Growth factors such as neurotrophins that promote the survival of neurons are known asneurotrophic factors. Neurotrophic factors are secreted by target tissue and act by preventing the associated neuron from initiatingprogrammed cell death – allowing the neurons to survive. Neurotrophins also induce differentiation ofprogenitor cells, toform neurons.
Although the vast majority of neurons in the mammalianbrain are formed prenatally, parts of the adult brain (for example, thehippocampus) retain the ability to grow new neurons from neuralstem cells, a process known asneurogenesis.[3] Neurotrophins are chemicals that help to stimulate and control neurogenesis.
According to theUnited States National Library of Medicine'smedical subject headings, the termneurotrophin may be used as a synonym forneurotrophic factor,[4] but the termneurotrophin is more generally reserved for four structurally related factors:nerve growth factor (NGF),brain-derived neurotrophic factor (BDNF),neurotrophin-3 (NT-3), andneurotrophin-4 (NT-4).[5] The termneurotrophic factor generally refers to these four neurotrophins, theGDNF family of ligands, andciliary neurotrophic factor (CNTF), among otherbiomolecules.[5] Neurotrophin-6 and neurotrophin-7 also exist, but are only found inzebrafish.[6]
During 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 outaxon outgrowths that contact their target cells.[7] 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 isnerve growth factor (NGF or beta-NGF), a vertebrate protein that stimulates division and differentiation ofsympathetic and embryonic sensory neurons.[8][9] NGF is mostly found outside thecentral nervous system (CNS), but slight traces have been detected in adult CNS tissues, although a physiological role for this is unknown.[7] It has also been found in several snake venoms.[10][11]
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 the nervous system to help keep nerve cells alive. There are two distinct classes ofglycosylated receptors that can bind to neurotrophins. These two proteins arep75 (NTR), which binds to all neurotrophins, and subtypes ofTrk, 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 theectodomain of glycosylated p75 (NRT), forming a symmetrical crystal structure.[citation needed]
There are two classes ofreceptors for neurotrophins:p75 and the"Trk" family ofTyrosine kinases receptors.[12]
Nerve growth factor (NGF), the prototypicalgrowth factor, is a protein secreted by a neuron's target cell. NGF is critical for the survival and maintenance ofsympathetic andsensory neurons. NGF is released from the target cells, binds to and activates its high affinity receptorTrkA on the neuron, and is internalized into the responsive neuron. The NGF/TrkA complex is subsequently trafficked back to the neuron'scell body. This movement of NGF fromaxon tip tosoma is thought to be involved in the long-distance signaling of neurons.[13]
Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor found originally in thebrain, but also found in the periphery. To be specific, it is a protein that has activity on certain neurons of thecentral 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 andsynapses throughaxonal anddendritic sprouting. In the brain, it is active in thehippocampus,cortex,cerebellum, and basalforebrain – areas vital to learning, memory, and higher thinking. BDNF was the second neurotrophic factor to be characterized, after NGF and before neurotrophin-3.[citation needed]
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 normalneural development.[citation needed]
Despite its name, BDNF 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.[14]
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 the peripheral andcentral nervous system; it helps to support the survival and differentiation of existing neurons, and encourages the growth and differentiation of new neurons andsynapses. NT-3 is the third neurotrophic factor to be characterized, after NGF and BDNF.[citation needed]
NT-3 is unique among the neurotrophins in the number of neurons it has potential to stimulate, given its ability to activate two of the receptor tyrosine kinase neurotrophin receptors (TrkC andTrkB). Mice born without the ability to makeNT-3 have loss of proprioceptive and subsets of mechanoreceptive sensory neurons.[citation needed]
Neurotrophin-4 (NT-4) is a neurotrophic factor that signals predominantly through theTrkBreceptor tyrosine kinase. It is also known as NT4, NT5, NTF4, and NT-4/5.[15]
Theendogenoussteroidsdehydroepiandrosterone (DHEA) and itssulfateester,DHEA sulfate (DHEA-S), have been identified assmall-moleculeagonists of the TrkA and p75NTR with highaffinity (around 5 nM), and hence as so-called "microneurotrophins".[16][17][18][19] 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.[16] It has been proposed that DHEA may have been the ancestral ligand of the Trk receptors early on in theevolution of thenervous system, eventually being superseded by the polypeptide neurotrophins.[16][18]
Duringneuron development neurotrophins play a key role in growth,differentiation, and survival.[20] They also play an important role in theapoptoticprogrammed cell death (PCD) of neurons.[21] Neurotrophic survival signals in neurons are mediated by the high-affinity binding of neurotrophins to their respective Trk receptor.[20] In turn, a majority of neuronal apoptotic signals are mediated by neurotrophins binding to thep75NTR.[21] The PCD which occurs duringbrain development is responsible for the loss of a majority ofneuroblasts and differentiating neurons.[20] It is necessary because during development there is a massive over production of neurons which must be killed off to attain optimal function.[20][21]
In the development of both theperipheral nervous system (PNS) and thecentral nervous system (CNS) the p75NTR-neurotrophin binding activates multipleintracellular pathways which are important in regulating apoptosis.[20][22] Proneurotrophins (proNTs) are neurotrophins which are released as biologically active uncleavedpro-peptides.[20] Unlike mature neurotrophins which bind to the p75NTR with a low affinity, proNTs preferentially bind to the p75NTR with high affinity.[23][24] The p75NTR contains adeath domain on itscytoplasmic tail which when cleaved activates an apoptotic pathway.[20][21][25] The binding of a proNT (proNGF or proBDNF) to p75NTR and itssortilinco-receptor (which binds the pro-domain of proNTs) causes a p75NTR-dependent signaltransduction cascade.[20][21][23][25] The cleaved death domain of p75NTR activatesc-Jun N-terminal kinase (JNK).[21][26][27] The activated JNK translocates into thenucleus, where itphosphorylates andtransactivatesc-Jun.[21][26] The transactivation of c-Jun results in the transcription of pro-apoptotic factorsTFF-a,Fas-L andBak.[20][21][23][25][26][27][28] 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.[23] Activation of p75NTR-mediated apoptosis is much more effective in the absence of Trk receptors due to the fact that activated Trk receptors suppress the JNK cascade.[27][29]
The expression ofTrkA orTrkC receptors in the absence of neurotrophins can lead to apoptosis, but the mechanism is poorly understood.[30] The addition ofNGF (for TrkA) orNT-3 (for TrkC) prevents this apoptosis.[30] For this reason TrkA and TrkC are referred to asdependence receptors, because whether they induce apoptosis or survival is dependent on the presence of neurotrophins.[21][31] The expression of TrkB, which is found mainly in the CNS, does not cause apoptosis.[21] This is thought to be because it is differentially located in the cell membrane while TrkA and TrkC are co-localized with p75NTR inlipid rafts.[21][30]
In the PNS (where NGF, NT-3 andNT-4 are mainly secreted)cell fate is determined by a singlegrowth factor (i.e. neurotrophins).[23][31] However, in the CNS (whereBDNF is mainly secreted in thespinal cord,substantia nigra,amygdala,hypothalamus,cerebellum,hippocampus andcortex) more factors determine cell fate, including neural activity andneurotransmitter input.[23][31] Neurotrophins in the CNS have also been shown to play a more important role in neuralcell differentiation and function rather than survival.[31] For these reasons, compared to neurons in 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 thethalamus andsubstantia nigra.[21]
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.[21] These knockout experiments resulted in the loss of several neuron populations including theretina,cholinergicbrainstem and thespinal cord.[21][23] It was found that NGF-knockout mice had losses of a majority of theirdorsal root ganglia (DRG),trigeminal ganglia andsuperior cervical ganglia.[21][27] Theviability of these mice was poor.[21] The BDNF-knockout mice had losses of a majority of theirvestibular ganglia and moderate losses of their DRG,[32] trigeminal ganglia, nodose petrosal ganglia and cochlear ganglia.[21][27] In addition they also had minor losses of theirfacial motoneurons located in the CNS.[21][27] The viability of these mice was moderate.[21] The NT-4-knockout mice had moderate losses of theirnodose petrosal ganglia and minor losses of their DRG, trigeminal ganglia and vestibular ganglia.[21][27] The NT-4-knockout mice also had minor losses of facial motoneurons.[21][27] These mice were very viable.[21] 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.[21][27] In addition the NT-3-knockout mice had moderate losses ofspinal moroneurons.[21][27] These mice had very poor viability.[21] These results show that the absence of different neurotrophins result in losses of different neuron populations (mainly in the PNS).[21] Furthermore, the absence of the neurotrophin survival signal leads to apoptosis.[21]
Neurotrophic factors are polypeptides or small proteins that support the growth, differentiation, and survival of neurons. They produce their effects by activation of tyrosine kinases.