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{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Redirect|NT3|the Microsoft operating system|Windows NT 3}}
{{Infobox gene}}

'''Neurotrophin-3''' is a [[protein]] that in humans is encoded by the ''NTF3'' [[gene]].<ref name="pmid1889806">{{cite journal | vauthors = Maisonpierre PC, ((Le Beau MM)), ((Espinosa R III)), Ip NY, Belluscio L, de la Monte SM, Squinto S, Furth ME, Yancopoulos GD | title = Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations | journal = Genomics | volume = 10 | issue = 3 | pages = 558–68 |date=Oct 1991 | pmid = 1889806 | doi =10.1016/0888-7543(91)90436-I  }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: NTF3 neurotrophin 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4908}}</ref>

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 [[neuron]]s 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 [[synapse]]s. NT-3 was the third neurotrophic factor to be characterized, after [[nerve growth factor]] (NGF) and [[BDNF]] (Brain Derived Neurotrophic Factor).<ref>{{cite journal |vauthors=Maisonpierre P, Belluscio L, Squinto S, Ip N, Furth M, Lindsay R, Yancopoulos G |title=Neurotrophin-3: a neurotrophic factor related to NGF and BDNF |journal=Science |volume=247 |issue=4949 Pt 1 |pages=1446–51 |year=1990 |pmid=2321006 |doi=10.1126/science.2321006|bibcode=1990Sci...247.1446M |s2cid=37763746 }}</ref>

==Function==
Although the vast majority of neurons in the [[mammal]]ian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural [[stem cell]]s; 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]]).<ref>{{cite journal | vauthors = Glass DJ, Nye SH, Hantzopoulos P, Macchi MJ, Squinto SP, Goldfarb M, Yancopoulos GD | title = TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor | journal = Cell | volume = 66 | issue = 2 | pages = 405–413 | date = July 1991 | pmid = 1649703 | doi =  10.1016/0092-8674(91)90629-d | s2cid = 43626580 }}</ref><ref>{{cite journal | vauthors = Ip NY, Stitt TN, Tapley P, Klein R, Glass DJ, Fandl J, Greene LA, Barbacid M, Yancopoulos GD | title = Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells | journal = Neuron | volume = 10 | issue = 2 | pages = 137–149 | date = Feb 1993 | pmid = 7679912 | doi = 10.1016/0896-6273(93)90306-c | s2cid = 46072027 }}</ref>

Mice born without the ability to make NT-3 have loss of [[proprioceptive]] and subsets of [[mechanoreceptive]] sensory neurons.<ref>{{cite journal |vauthors=Tessarollo L, Vogel K, Palko M, Reid S, Parada L |title=Targeted mutation in the neurotrophin-3 gene results in loss of muscle sensory neurons |journal=Proc Natl Acad Sci USA |volume=91 |issue=25 |pages=11844–8 |year=1994 |pmid=7991545 |doi=10.1073/pnas.91.25.11844 |pmc=45332|bibcode=1994PNAS...9111844T |doi-access=free }}</ref><ref>{{cite journal |vauthors=Klein R, Silos-Santiago I, Smeyne R, Lira S, Brambilla R, Bryant S, Zhang L, Snider W, Barbacid M |title=Disruption of the neurotrophin-3 receptor gene trkC eliminates la muscle afferents and results in abnormal movements |journal=Nature |volume=368 |issue=6468 |pages=249–51 |year=1994 |pmid=8145824 |doi=10.1038/368249a0|bibcode=1994Natur.368..249K |s2cid=4328770 }}</ref>

==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.<ref>{{cite journal |vauthors=Lamballe F, Klein R, Barbacid M |title=trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3 |journal=Cell |volume=66 |issue=5 |pages=967–79 |year=1991 |pmid=1653651 |doi=10.1016/0092-8674(91)90442-2|s2cid=23448391 }}</ref><ref>{{cite journal |vauthors=Tessarollo L, Tsoulfas P, Martin-Zanca D, Gilbert D, Jenkins N, Copeland N, Parada L |title=trkC, a receptor for neurotrophin-3, is widely expressed in the developing nervous system and in non-neuronal tissues |journal=Development |volume=118 |issue=2 |pages=463–75 |year=1993 |doi=10.1242/dev.118.2.463 |pmid=8223273}}</ref>
* However, NT-3 is capable of binding and signaling through a TrkC-related receptors called [[TrkB]].<ref>{{cite journal | vauthors = Glass DJ, Nye SH, Hantzopoulos P, Macchi MJ, Squinto SP, Goldfarb M, Yancopoulos GD | title = TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor | journal = Cell | volume = 66 | issue = 2 | pages = 405–413 | date = July 1991 | pmid = 1649703 | doi =  10.1016/0092-8674(91)90629-d | s2cid = 43626580 }}</ref>
* 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:  
* [[nerve growth factor|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 [[Nerve growth factor|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.<ref>{{cite journal |vauthors=Gong Y, Cao P, Yu HJ, Jiang T |title=Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex |journal=Nature |volume=454 |issue=7205 |pages=789–93 |date=August 2008 |pmid=18596692 |doi=10.1038/nature07089 |bibcode=2008Natur.454..789G |s2cid=4333271 }}</ref>

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|Tropomyosin receptor kinase B § Agonists]]

==References==
{{Reflist}}

==Further reading==
{{refbegin|35em}}
*{{cite journal  |vauthors=Kalcheim C, Carmeli C, Rosenthal A |title=Neurotrophin 3 is a mitogen for cultured neural crest cells. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=89 |issue= 5 |pages= 1661–5 |year= 1992 |pmid= 1542658 |doi=10.1073/pnas.89.5.1661  | pmc=48512  |bibcode=1992PNAS...89.1661K |doi-access=free }}
*{{cite journal  |vauthors=Ozçelik T, Rosenthal A, Francke U |title=Chromosomal mapping of brain-derived neurotrophic factor and neurotrophin-3 genes in man and mouse. |journal=Genomics |volume=10 |issue= 3 |pages= 569–75 |year= 1991 |pmid= 1889807 |doi=10.1016/0888-7543(91)90437-J  }}
*{{cite journal  |vauthors=Hallböök F, Ibáñez CF, Persson H |title=Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary. |journal=Neuron |volume=6 |issue= 5 |pages= 845–58 |year= 1991 |pmid= 2025430 |doi=10.1016/0896-6273(91)90180-8  |s2cid=17772282 }}
*{{cite journal  |vauthors=Jones KR, Reichardt LF |title=Molecular cloning of a human gene that is a member of the nerve growth factor family. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=87 |issue= 20 |pages= 8060–4 |year= 1990 |pmid= 2236018 |doi=10.1073/pnas.87.20.8060  | pmc=54892  |bibcode=1990PNAS...87.8060J |doi-access=free }}
*{{cite journal   |vauthors=Rosenthal A, Goeddel DV, Nguyen T, etal |title=Primary structure and biological activity of a novel human neurotrophic factor. |journal=Neuron |volume=4 |issue= 5 |pages= 767–73 |year= 1990 |pmid= 2344409 |doi=10.1016/0896-6273(90)90203-R  |s2cid=30148948 }}
*{{cite journal  |vauthors=Kaisho Y, Yoshimura K, Nakahama K |title=Cloning and expression of a cDNA encoding a novel human neurotrophic factor. |journal=FEBS Lett. |volume=266 |issue= 1–2 |pages= 187–91 |year= 1990 |pmid= 2365067 |doi=10.1016/0014-5793(90)81536-W  |s2cid=7645464 |doi-access=free }}
*{{cite journal  |vauthors=Ernfors P, Lee KF, Kucera J, Jaenisch R |title=Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. |journal=Cell |volume=77 |issue= 4 |pages= 503–12 |year= 1994 |pmid= 7514502 |doi=10.1016/0092-8674(94)90213-5  |s2cid=9072110 }}
*{{cite journal  |vauthors=Robinson RC, Radziejewski C, Stuart DI, Jones EY |title=Structure of the brain-derived neurotrophic factor/neurotrophin 3 heterodimer. |journal=Biochemistry |volume=34 |issue= 13 |pages= 4139–46 |year= 1995 |pmid= 7703225 |doi=10.1021/bi00013a001  }}
*{{cite journal  |vauthors=Hattori M, Nanko S |title=Association of neurotrophin-3 gene variant with severe forms of schizophrenia. |journal=Biochem. Biophys. Res. Commun. |volume=209 |issue= 2 |pages= 513–8 |year= 1995 |pmid= 7733919 |doi= 10.1006/bbrc.1995.1531 }}
*{{cite journal   |vauthors=Tessarollo L, Vogel KS, Palko ME, etal |title=Targeted mutation in the neurotrophin-3 gene results in loss of muscle sensory neurons. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=91 |issue= 25 |pages= 11844–8 |year= 1995 |pmid= 7991545 |doi=10.1073/pnas.91.25.11844  | pmc=45332  |bibcode=1994PNAS...9111844T |doi-access=free }}
*{{cite journal  |vauthors=Rydén M, Ibáñez CF |title=Binding of neurotrophin-3 to p75LNGFR, TrkA, and TrkB mediated by a single functional epitope distinct from that recognized by trkC. |journal=J. Biol. Chem. |volume=271 |issue= 10 |pages= 5623–7 |year= 1996 |pmid= 8621424 |doi=10.1074/jbc.271.10.5623  |doi-access=free }}
*{{cite journal   |vauthors=Hui JO, Le J, Katta V, etal |title=Human neurotrophin-3: a one-step peptide mapping method and complete disulfide characterization of the recombinant protein. |journal=J. Protein Chem. |volume=15 |issue= 4 |pages= 351–8 |year= 1996 |pmid= 8819011 |doi=10.1007/BF01886861  |s2cid=34957071 }}
*{{cite journal  |vauthors=Donovan MJ, Hahn R, Tessarollo L, Hempstead BL |title=Identification of an essential nonneuronal function of neurotrophin 3 in mammalian cardiac development. |journal=Nat. Genet. |volume=14 |issue= 2 |pages= 210–3 |year= 1996 |pmid= 8841198 |doi= 10.1038/ng1096-210 |s2cid=9259115 |url=https://zenodo.org/record/1233403 }}
*{{cite journal   |vauthors=Arinami T, Takekoshi K, Itokawa M, etal |title=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. |journal=Psychiatr. Genet. |volume=6 |issue= 1 |pages= 13–5 |year= 1996 |pmid= 8925252 |doi=10.1097/00041444-199621000-00003  |s2cid=42610869 }}
*{{cite journal   |vauthors=Urfer R, Tsoulfas P, O'Connell L, etal |title=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. |journal=J. Biol. Chem. |volume=273 |issue= 10 |pages= 5829–40 |year= 1998 |pmid= 9488719 |doi=10.1074/jbc.273.10.5829  |doi-access=free }}
*{{cite journal   |vauthors=Suenaga M, Ohmae H, Tsuji S, etal |title=Renaturation of recombinant human neurotrophin-3 from inclusion bodies using a suppressor agent of aggregation. |journal=Biotechnol. Appl. Biochem. |volume=28 |issue=  2|pages= 119–24 |year= 1998 |doi=10.1111/j.1470-8744.1998.tb00521.x |pmid= 9756741 |s2cid=45466609 }}
*{{cite journal   |vauthors=Hochhaus F, Koehne P, Schäper C, etal |title=Elevated nerve growth factor and neurotrophin-3 levels in cerebrospinal fluid of children with hydrocephalus. |journal=BMC Pediatrics |volume=1 |pages= 2 |year= 2003 |pmid= 11580868 |doi=10.1186/1471-2431-1-2  | pmc=57003  |doi-access=free }}
*{{cite journal  |vauthors=Kobayashi H, Gleich GJ, Butterfield JH, Kita H |title=Human eosinophils produce neurotrophins and secrete nerve growth factor on immunologic stimuli. |journal=Blood |volume=99 |issue= 6 |pages= 2214–20 |year= 2002 |pmid= 11877300 |doi=10.1182/blood.V99.6.2214  |doi-access=free }}
*{{cite journal   |vauthors=Hattori M, Kunugi H, Akahane A, etal |title=Novel polymorphisms in the promoter region of the neurotrophin-3 gene and their associations with schizophrenia. |journal=Am. J. Med. Genet. |volume=114 |issue= 3 |pages= 304–9 |year= 2002 |pmid= 11920853 |doi=10.1002/ajmg.10248  }}
{{refend}}
{{PDB Gallery|geneid=4908}}

{{Hormones}}
{{Nerve growth factor family}}
{{Growth factor receptor modulators}}

[[Category:Neurotrophic factors]]
[[Category:Peptide hormones]]
[[Category:Growth factors]]
[[Category:Developmental neuroscience]]
[[Category:Proteins]]
[[Category:TrkB agonists]]

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