NEUROTROPHIN-3, HUMAN

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.

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. 

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).

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.

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).

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.

Neurotrophin-3 is the third neurotrophic factor, characterized after nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). NT-3 is a polypeptide consisting of 119 amino acid residues, and forms a homodimer. NT-3 binds to tropomyosin receptor kinase C (TrkC) with high affinity. NT-3 also binds to TrkA, TrkB, and p75NTR with low affinity. NT-3 promotes the differentiation, growth, and survival of neurons. The distribution of NT-3 and its biological activity on a variety of neuronal populations clearly distinguish NT-3 from NGF and BDNF, indicating that NT-3 is an authentic neurotrophic factor that has its own characteristic role in vivo.

NT-3 (neurotrophin 3) is a neurotrophic factor structurally related to β-NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor), and NT-4. These proteins belong to the cysteine-knot family of growth factors that assume stable dimeric structures. NT-3 is expressed by neurons of the central nervous systems and can signal through the trk receptors. Recombinant human NT-3 is a noncovalently linked homodimer, of two 13.6kDa polypeptide monomers (240 total amino acid residues). The amino acid sequences of human, murine and rat NT-3 are identical.

NT-3 (neurotrophin 3) promotes the growth and survival of nerve and glial cells. It is associated with neuroprotection and polymorphisms in the gene are associated with risk to Alzheimer′s disease. It is also linked with attention-deficit/hyperactivity disorder (ADHD) and mood disorders. NT-3 enhances the metastatic proliferation of breast cancer cells in the brain.

NT-3 shows protective effects against acoustic neurotoxicity by aminoglycoside antibiotics. Currently, NT-3 is being investigated in clinical trials as a treatment for peripheral neuropathies, including Charcot-Marie Tooth neuropathy, and it is also expected to be useful in the treatment of injured spinal cords.