Neurotrophin-3

"NT3" redirects here. For the Microsoft operating system, see Windows NT 3.

Neurotrophin-3 is a protein that in humans is encoded by the NTF3 gene.

NTF3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1B8K, 1BND, 1NT3, 3BUK
Identifiers
Aliases	NTF3, HDNF, NGF-2, NGF2, NT-3, NT3, neurotrophin 3
External IDs	OMIM: 162660; MGI: 97380; HomoloGene: 1896; GeneCards: NTF3; OMA:NTF3 - orthologs
Gene location (Human) Chr. Chromosome 12 (human) Band 12p13.31 Start 5,432,108 bp End 5,521,536 bp
Gene location (Mouse) Chr. Chromosome 6 (mouse) Band 6 F3|6 60.45 cM Start 126,078,375 bp End 126,143,873 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in popliteal artery tibial arteries right coronary artery ascending aorta left coronary artery Descending thoracic aorta right ovary left ovary testicle saphenous vein Top expressed in external naris ciliary body ascending aorta iris corneal stroma conjunctival fornix maxillary prominence substantia nigra pineal gland medullary collecting duct More reference expression data BioGPS More reference expression data
Gene ontology Molecular function neurotrophin p75 receptor binding neurotrophin receptor binding chemoattractant activity growth factor activity signaling receptor binding protein binding Cellular component cytoplasmic vesicle extracellular region extracellular space synaptic vesicle axon dendrite Biological process regulation of apoptotic process negative regulation of neuron apoptotic process regulation of neuron differentiation activation of protein kinase B activity neuron projection morphogenesis activation of GTPase activity positive regulation of receptor internalization transmembrane receptor protein tyrosine kinase signaling pathway positive regulation of cell migration cell-cell signaling positive regulation of peptidyl-serine phosphorylation induction of positive chemotaxis negative regulation of peptidyl-tyrosine phosphorylation positive regulation of cell population proliferation positive regulation of peptidyl-tyrosine phosphorylation positive regulation of actin cytoskeleton reorganization signal transduction positive chemotaxis nervous system development regulation of signaling receptor activity positive regulation of phospholipase C activity positive regulation of phosphatidylinositol 3-kinase signaling peripheral nervous system development memory nerve development nerve growth factor signaling pathway modulation of chemical synaptic transmission positive regulation of neurotrophin TRK receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4908 18205 Ensembl ENSG00000185652 ENSMUSG00000049107 UniProt P20783 P20181 RefSeq (mRNA) NM_001102654 NM_002527 NM_001164034 NM_001164035 NM_008742 RefSeq (protein) NP_001096124 NP_002518 NP_001157506 NP_001157507 NP_032768 Location (UCSC) Chr 12: 5.43 – 5.52 Mb Chr 6: 126.08 – 126.14 Mb PubMed search
Wikidata
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The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activity on certain neurons of 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 was the third neurotrophic factor to be characterized, after nerve growth factor (NGF) and BDNF (Brain Derived Neurotrophic Factor).

Function

Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain 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.

NT-3 is unique in the number of neurons it can potentially stimulate, given its ability to activate two of 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.

Mechanism of action

NT-3 binds three receptors on the surface of cells which are capable of responding to this growth factor:

• TrkC (pronounced "Track C"), is apparently the "physiologic" receptor, in that it binds with greatest affinity to NT-3.
• However, NT-3 is capable of binding and signaling through a TrkC-related receptors called TrkB.
• Finally, NT-3 also binds a second-receptor type besides Trk receptors, called the LNGFR (for "low affinity nerve growth factor receptor).

High affinity receptors

TrkC is a receptor tyrosine kinase (meaning it mediates its actions by causing the addition of phosphate molecules on certain tyrosines in the cell, activating cellular signaling).

As mentioned above, there are other related Trk receptors, TrkA and TrkB. Also as mentioned, there are other neurotrophic factors structurally related to NT-3:

• NGF (for "Nerve Growth Factor")
• BDNF (for "Brain Derived Neurotrophic Factor")
• NT-4 (for "Neurotrophin-4")

While TrkB mediates the effects of BDNF, NT-4, and NT-3, TrkA binds and is activated by NGF, and TrkC binds and is activated only by NT-3.

Low affinity receptors

The other NT-3 receptor, the LNGFR, plays a somewhat less clear role. Some researchers have shown the LNGFR binds and serves as a "sink" for neurotrophins.

The crystal structure of NT-3 shows that NT-3 forms a central homodimer around which two glycosylated p75 LNGFR molecules bind symmetrically. The symmetrical binding takes place along the NT-3 interfaces, resulting in a 2:2 ligand-receptor cluster in the center.

Cells which express both the LNGFR and the Trk receptors might therefore have a greater activity – since they have a higher "microconcentration" of the neurotrophin.

It has also been shown, however, that the LNGFR may signal a cell to die via apoptosis – so therefore cells expressing the LNGFR in the absence of Trk receptors may die rather than live in the presence of a neurotrophin.

See also

• Tropomyosin receptor kinase B § Agonists

Further reading

• Kalcheim C, Carmeli C, Rosenthal A (1992). "Neurotrophin 3 is a mitogen for cultured neural crest cells". Proc. Natl. Acad. Sci. U.S.A. 89 (5): 1661–5. Bibcode:1992PNAS...89.1661K. doi:10.1073/pnas.89.5.1661. PMC 48512. PMID 1542658.
• Ozçelik T, Rosenthal A, Francke U (1991). "Chromosomal mapping of brain-derived neurotrophic factor and neurotrophin-3 genes in man and mouse". Genomics. 10 (3): 569–75. doi:10.1016/0888-7543(91)90437-J. PMID 1889807.
• Hallböök F, Ibáñez CF, Persson H (1991). "Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary". Neuron. 6 (5): 845–58. doi:10.1016/0896-6273(91)90180-8. PMID 2025430. S2CID 17772282.
• Jones KR, Reichardt LF (1990). "Molecular cloning of a human gene that is a member of the nerve growth factor family". Proc. Natl. Acad. Sci. U.S.A. 87 (20): 8060–4. Bibcode:1990PNAS...87.8060J. doi:10.1073/pnas.87.20.8060. PMC 54892. PMID 2236018.
• Rosenthal A, Goeddel DV, Nguyen T, et al. (1990). "Primary structure and biological activity of a novel human neurotrophic factor". Neuron. 4 (5): 767–73. doi:10.1016/0896-6273(90)90203-R. PMID 2344409. S2CID 30148948.
• Kaisho Y, Yoshimura K, Nakahama K (1990). "Cloning and expression of a cDNA encoding a novel human neurotrophic factor". FEBS Lett. 266 (1–2): 187–91. doi:10.1016/0014-5793(90)81536-W. PMID 2365067. S2CID 7645464.
• Ernfors P, Lee KF, Kucera J, Jaenisch R (1994). "Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents". Cell. 77 (4): 503–12. doi:10.1016/0092-8674(94)90213-5. PMID 7514502. S2CID 9072110.
• Robinson RC, Radziejewski C, Stuart DI, Jones EY (1995). "Structure of the brain-derived neurotrophic factor/neurotrophin 3 heterodimer". Biochemistry. 34 (13): 4139–46. doi:10.1021/bi00013a001. PMID 7703225.
• Hattori M, Nanko S (1995). "Association of neurotrophin-3 gene variant with severe forms of schizophrenia". Biochem. Biophys. Res. Commun. 209 (2): 513–8. doi:10.1006/bbrc.1995.1531. PMID 7733919.
• Tessarollo L, Vogel KS, Palko ME, et al. (1995). "Targeted mutation in the neurotrophin-3 gene results in loss of muscle sensory neurons". Proc. Natl. Acad. Sci. U.S.A. 91 (25): 11844–8. Bibcode:1994PNAS...9111844T. doi:10.1073/pnas.91.25.11844. PMC 45332. PMID 7991545.
• Rydén M, Ibáñez CF (1996). "Binding of neurotrophin-3 to p75LNGFR, TrkA, and TrkB mediated by a single functional epitope distinct from that recognized by trkC". J. Biol. Chem. 271 (10): 5623–7. doi:10.1074/jbc.271.10.5623. PMID 8621424.
• Hui JO, Le J, Katta V, et al. (1996). "Human neurotrophin-3: a one-step peptide mapping method and complete disulfide characterization of the recombinant protein". J. Protein Chem. 15 (4): 351–8. doi:10.1007/BF01886861. PMID 8819011. S2CID 34957071.
• Donovan MJ, Hahn R, Tessarollo L, Hempstead BL (1996). "Identification of an essential nonneuronal function of neurotrophin 3 in mammalian cardiac development". Nat. Genet. 14 (2): 210–3. doi:10.1038/ng1096-210. PMID 8841198. S2CID 9259115.
• Arinami T, Takekoshi K, Itokawa M, et al. (1996). "Failure to find associations of the CA repeat polymorphism in the first intron and the Gly-63/Glu-63 polymorphism of the neurotrophin-3 gene with schizophrenia". Psychiatr. Genet. 6 (1): 13–5. doi:10.1097/00041444-199621000-00003. PMID 8925252. S2CID 42610869.
• Urfer R, Tsoulfas P, O'Connell L, et al. (1998). "High resolution mapping of the binding site of TrkA for nerve growth factor and TrkC for neurotrophin-3 on the second immunoglobulin-like domain of the Trk receptors". J. Biol. Chem. 273 (10): 5829–40. doi:10.1074/jbc.273.10.5829. PMID 9488719.
• Suenaga M, Ohmae H, Tsuji S, et al. (1998). "Renaturation of recombinant human neurotrophin-3 from inclusion bodies using a suppressor agent of aggregation". Biotechnol. Appl. Biochem. 28 (2): 119–24. doi:10.1111/j.1470-8744.1998.tb00521.x. PMID 9756741. S2CID 45466609.
• Hochhaus F, Koehne P, Schäper C, et al. (2003). "Elevated nerve growth factor and neurotrophin-3 levels in cerebrospinal fluid of children with hydrocephalus". BMC Pediatrics. 1: 2. doi:10.1186/1471-2431-1-2. PMC 57003. PMID 11580868.
• Kobayashi H, Gleich GJ, Butterfield JH, Kita H (2002). "Human eosinophils produce neurotrophins and secrete nerve growth factor on immunologic stimuli". Blood. 99 (6): 2214–20. doi:10.1182/blood.V99.6.2214. PMID 11877300.
• Hattori M, Kunugi H, Akahane A, et al. (2002). "Novel polymorphisms in the promoter region of the neurotrophin-3 gene and their associations with schizophrenia". Am. J. Med. Genet. 114 (3): 304–9. doi:10.1002/ajmg.10248. PMID 11920853.