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Questions And Answer

• Discovery

  By the 1980s, NGF and BDNF had been isolated and characterized. The structural similarity between NGF and BDNF and their restricted neuronal specificity suggest that additional and functionally distinct members of this family might exist. Then, taking advantage of sequence identities between NGF and BDNF and polymerase chain reaction, Hohn et al. identified a third member of this family, named neurotrophin-3 (NT-3) in 1990. Within 3 months after the publication of the study, five studies on the cloning and identification of NT-3 were published.;

• Structure

  NT-3 is a polypeptide consisting of 119 aa residues. The human NTF3 gene encodes a preproprotein of 257 aa residues (preproNT-3) . After cleavage, the mature NT-3 dimerizes through noncovalent interaction. NT-3 has been identified in mammals, birds, reptiles, amphibians, and teleosts. The amino acid sequences of NT-3 are highly conserved among vertebrates. Mammalian NT-3 has 100% homology. Six cysteines involved in the intramolecular disulfide bond are conserved among all vertebrate NT-3s. 
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• Properties

  Mr. 27,453 (mammalian preproNT-3); 13,625 (mammalian mature NT-3). pI=9.3. NT-3 is soluble in water. Disulfide bridges are formed between Cys14 and Cys79, between Cys57 and Cys108, and between Cys67 and Cys110 (in mammalian mature NT-3).;

• Gene, mRNA, and precursor

  The human proNT-3 gene, NTF3, location 12p13.31, consists of three exons. The human NT-3 mRNA has 1182 bases that encode a preproNT-3 of 257 aa residues. ProNT-3 shows broad expression in the ovary (RPKM 4.8), spleen (RPKM 2.1), and 19 other tissues including the heart, liver, pancreas, kidney, and brain. In the brain, higher levels of expression are observed in the hippocampus, cerebellum, olfactory bulb, and septam.;

• Receptors

  NT-3 binds to tropomyosin receptor kinase C (TrkC) with high affinity, and to TrkA, TrkB, and p75NTR with low affinity. These receptors are singletransmembrane receptors. Unlike TrkA, TrkB, and p75NTR, TrkC binds specifically to NT-3. The human NTRK3 gene encodes TrkC of 839 aa residues. The human NGFR gene encodes p75NTR of 427 aa residues. TrkC has a tyrosine-kinase domain in the cytoplasmic region. There are truncated isoforms lacking the tyrosine-kinase domain. p75NTR has no tyrosine-kinase domain. The binding activity of mature NT-3: Kd=10 pM (TrkC) and 1 nM (p75NTR).
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• Biological functions

  TrkC shows a biased expression in the brain (RPKM 2.8), the fat (RPKM 1.2), and 13 other tissues, including the endometrium and testis. Prominent expression of TrkC gene is observed in the hippocampus, cerebral cortex, and the granular cell layer of the cerebellum. The activation of TrkC promotes the survival and differentiation of existing neurons and the growth and differentiation of new neurons. NT-3 also enhances synaptic transmission in the rat hippocampal slices. The role of p75NTR in NT-3 signaling is less clear.;

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