Hormones, LNGF (p75NTR)
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Neurotrophin-3 and Neurotrophin-4

Neurotrophin-4 (NT-4), also known as neurotrophin-5 (NT-5), is a protein that in humans is encoded by the NTF4 gene. It is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase. NT-4 was first discovered and isolated from xenopus and viper in the year 1991 by Finn Hallbook et.al

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

  • Glass DJ, Nye SH, Hantzopoulos P, Macchi MJ, Squinto SP, Goldfarb M, Yancopoulos GD (July 1991). “TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor”. Cell. 66 (2): 405–413. doi:10.1016/0092-8674(91)90629-d. PMID 1649703. S2CID 43626580.
  • Ip NY, Stitt TN, Tapley P, Klein R, Glass DJ, Fandl J, Greene LA, Barbacid M, Yancopoulos GD (Feb 1993). “Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells”. Neuron. 10 (2): 137–149. doi:10.1016/0896-6273(93)90306-c. PMID 7679912. S2CID 46072027.

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.
    • Lamballe F, Klein R, Barbacid M (1991). “trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3“. Cell. 66 (5): 967–79. doi:10.1016/0092-8674(91)90442-2. PMID 1653651. S2CID 23448391.
    • Tessarollo L, Tsoulfas P, Martin-Zanca D, Gilbert D, Jenkins N, Copeland N, Parada L (1993). “trkC, a receptor for neurotrophin-3, is widely expressed in the developing nervous system and in non-neuronal tissues“. Development. 118 (2): 463–75. doi:10.1242/dev.118.2.463. PMID 8223273.
  • However, NT-3 is capable of binding and signaling through a TrkC-related receptors called TrkB.
    • Glass DJ, Nye SH, Hantzopoulos P, Macchi MJ, Squinto SP, Goldfarb M, Yancopoulos GD (July 1991). “TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor“. Cell. 66 (2): 405–413. doi:10.1016/0092-8674(91)90629-d. PMID 1649703. S2CID 43626580.
  • 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[edit]

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

References

  1.  GRCh38: Ensembl release 89: ENSG00000225950 – Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000074121 – Ensembl, May 2017
  3. “Human PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. “Mouse PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Ibáñez CF, Ernfors P, Timmusk T, Ip NY, Arenas E, Yancopoulos GD, Persson H (April 1993). “Neurotrophin-4 is a target-derived neurotrophic factor for neurons of the trigeminal ganglion”. Development. 117 (4): 1345–1353. doi:10.1242/dev.117.4.1345. PMID 8404536.
  6. “Entrez Gene: neurotrophin 4”.
  7. Klein R, Lamballe F, Bryant S, Barbacid M (May 1992). “The trkB tyrosine protein kinase is a receptor for neurotrophin-4”. Neuron. 8 (5): 947–956. doi:10.1016/0896-6273(92)90209-v. PMID 1375038. S2CID 9772551.
  8. Ip NY, Stitt TN, Tapley P, Klein R, Glass DJ, Fandl J, et al. (February 1993). “Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells”. Neuron. 10 (2): 137–149. doi:10.1016/0896-6273(93)90306-c. PMID 7679912. S2CID 46072027.
  9. Hallböök F, Ibáñez CF, Persson H (May 1991). “Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary”. Neuron. 6 (5): 845–858. doi:10.1016/0896-6273(91)90180-8. PMID 2025430. S2CID 17772282.
  10. GRCh38: Ensembl release 89: ENSG00000185652 – Ensembl, May 2017
  11. GRCm38: Ensembl release 89: ENSMUSG00000049107 – Ensembl, May 2017
  12. “Human PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
  13. “Mouse PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
  14. Maisonpierre PC, Le Beau MM, Espinosa R III, Ip NY, Belluscio L, de la Monte SM, Squinto S, Furth ME, Yancopoulos GD (Oct 1991). “Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations”. Genomics. 10 (3): 558–68. doi:10.1016/0888-7543(91)90436-I. PMID 1889806.
  15. “Entrez Gene: NTF3 neurotrophin 3”.
  16. Maisonpierre P, Belluscio L, Squinto S, Ip N, Furth M, Lindsay R, Yancopoulos G (1990). “Neurotrophin-3: a neurotrophic factor related to NGF and BDNF”. Science. 247 (4949 Pt 1): 1446–51. Bibcode:1990Sci…247.1446M. doi:10.1126/science.2321006. PMID 2321006. S2CID 37763746.
  17. Glass DJ, Nye SH, Hantzopoulos P, Macchi MJ, Squinto SP, Goldfarb M, Yancopoulos GD (July 1991). “TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor”. Cell. 66 (2): 405–413. doi:10.1016/0092-8674(91)90629-d. PMID 1649703. S2CID 43626580.
  18. Ip NY, Stitt TN, Tapley P, Klein R, Glass DJ, Fandl J, Greene LA, Barbacid M, Yancopoulos GD (Feb 1993). “Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells”. Neuron. 10 (2): 137–149. doi:10.1016/0896-6273(93)90306-c. PMID 7679912. S2CID 46072027.
  19. Tessarollo L, Vogel K, Palko M, Reid S, Parada L (1994). “Targeted mutation in the neurotrophin-3 gene results in loss of muscle sensory neurons”. Proc Natl Acad Sci USA. 91 (25): 11844–8. Bibcode:1994PNAS…9111844T. doi:10.1073/pnas.91.25.11844. PMC 45332. PMID 7991545.
  20. Klein R, Silos-Santiago I, Smeyne R, Lira S, Brambilla R, Bryant S, Zhang L, Snider W, Barbacid M (1994). “Disruption of the neurotrophin-3 receptor gene trkC eliminates la muscle afferents and results in abnormal movements”. Nature. 368 (6468): 249–51. Bibcode:1994Natur.368..249K. doi:10.1038/368249a0. PMID 8145824. S2CID 4328770.
  21. Lamballe F, Klein R, Barbacid M (1991). “trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3”. Cell. 66 (5): 967–79. doi:10.1016/0092-8674(91)90442-2. PMID 1653651. S2CID 23448391.
  22. Tessarollo L, Tsoulfas P, Martin-Zanca D, Gilbert D, Jenkins N, Copeland N, Parada L (1993). “trkC, a receptor for neurotrophin-3, is widely expressed in the developing nervous system and in non-neuronal tissues”. Development. 118 (2): 463–75. doi:10.1242/dev.118.2.463. PMID 8223273.
  23. Glass DJ, Nye SH, Hantzopoulos P, Macchi MJ, Squinto SP, Goldfarb M, Yancopoulos GD (July 1991). “TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor”. Cell. 66 (2): 405–413. doi:10.1016/0092-8674(91)90629-d. PMID 1649703. S2CID 43626580.
  24. Gong Y, Cao P, Yu HJ, Jiang T (August 2008). “Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex”. Nature. 454 (7205): 789–93. Bibcode:2008Natur.454..789G. doi:10.1038/nature07089. PMID 18596692. S2CID 4333271.

Further reading (Neurotrophin-3)

Further reading (Neurotrophin-4)

External links

Hormones
Cell signaling: Nervous tissue: Neurotrophic factors
Growth factor receptor modulators

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