Alternative titles; symbols
HGNC Approved Gene Symbol: NTF3
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:5,430,332-5,495,299 (from NCBI)
For background information on neurotrophins and their receptors, see NGFR (162010).
Because of the close amino acid and nucleotide sequence similarity of nerve growth factor (NGF; 162030) and brain-derived neurotrophic factor (BDNF; 113505), Jones and Reichardt (1990) suspected that these neurotrophic factors are part of a larger gene family and searched for other members of the family by a screen involving the polymerase chain reaction (PCR) and low stringency hybridization with degenerate oligonucleotides. In this way, they identified a third gene, neurotrophin-3, that is closely related to both NGF and BDNF. mRNA products of both BDNF and NTF3 were detected in the adult human brain, suggesting that these proteins are involved in the maintenance of the adult nervous system. All 3 neurotrophic factors were also detected in human placenta, suggesting that the placenta, which is not innervated, may serve as a source for release of neurotrophic factors into the fetal bloodstream, where they affect development of neurons in the embryo. Kaisho et al. (1990) cloned a cDNA encoding the same human neurotrophic factor from a human glioma cDNA library using a synthetic DNA corresponding to human NGF. The cloned cDNA encodes a polypeptide comprising 257 amino acid residues, including a prepro-sequence of 138 residues and a mature region of 119 residues. The amino acid sequence showed a 58% similarity with that of human NGF. Maisonpierre et al. (1991) isolated the human NTF3 gene and demonstrated that its mature form was identical in all mammals examined.
Maisonpierre et al. (1991) localized the NTF3 gene to 12p13. The BDNF gene maps to 11p13. Thus, this is another example of the homeology of chromosomes 11 and 12. By analysis of hybrid cell lines, Ozcelik et al. (1991) also assigned the NTF3 gene to 12p. They assigned the equivalent gene in the mouse to chromosome 6.
Kalcheim et al. (1992) demonstrated that NTF3 promotes the survival of, and induces neurite outgrowth from, a subset of neural crest and placode-derived neurons. It regulates the proliferation of cultured neural crest progenitor cells grown in a serum-free defined medium.
The arrest of dorsal root axonal regeneration at the transitional zone between the peripheral and central nervous system has been repeatedly described. Ramer et al. (2000) demonstrated that with trophic support to damaged sensory axons, this regenerative barrier is surmountable. In adult rats with injured dorsal roots, treatment with NGF (162030), NTF3, or glial cell line-derived neurotrophic factor (GDNF; 600837), but not BDNF, resulted in selective regrowth of damaged axons across the dorsal root entry zone and into the spinal cord. Dorsal horn neurons were found to be synaptically driven by peripheral nerve stimulation in rats treated with NGF, NT3, and GDNF, demonstrating functional reconnection. In behavioral studies, rats treated with NGF and GDNF recovered sensitivity to noxious heat and pressure. Ramer et al. (2000) concluded that neurotrophic factor treatment may serve as a viable treatment in promoting recovery from root avulsion injuries.
Schwann cells in developing and regenerating peripheral nerves express elevated levels of the neurotrophin receptor p75(NTR) (162010). Neurotrophins are key mediators of peripheral nervous system myelination. Cosgaya et al. (2002) demonstrated that myelin formation is inhibited in the absence of functional p75(NTR) and enhanced by blocking TRKC (191316) activity. Moreover, the enhancement of myelin formation by endogenous BDNF is mediated by the p75(NTR) receptor, whereas TRKC receptors are responsible for NT3 inhibition. Thus, Cosgaya et al. (2002) concluded that p75(NTR) and TRKC receptors have opposite effects on myelination. Cosgaya et al. (2002) developed a model for the actions of endogenous neurotrophins and their receptors throughout myelination. During glial proliferation, elongation, and ensheathment, NT3 levels decrease whereas TRKC and p57(NTR) remain constant. The activation of TRKC by NT3 during these phases prevents the myelination program from proceeding. When myelination is initiated, NT3 protein levels have already become undetectable, thereby removing its inhibitory action. At the same time, BDNF acts as a positive modulator of myelination through the activation of p75(NTR). Once active myelination is underway, extracellular BDNF is removed through its binding to the increased levels of TRKB-T1 (600456). After the myelination is complete, all the neurotrophins and their receptors are downregulated.
Kuruvilla et al. (2004) found that the related neurotrophins NGF and NT3, acting through a common receptor, TRKA (191315), were required for sequential stages of sympathetic axon growth and, thus, innervation of target fields. Yet, while NGF supported TRKA internalization and retrograde signaling from distal axons to cell bodies to promote neuronal survival, NT3 could not. Final target-derived NGF promoted expression of the p75 neurotrophin receptor, in turn causing a reduction in the sensitivity of axons to intermediate target-derived NT3. Kuruvilla et al. (2004) proposed that a hierarchical neurotrophin signaling cascade coordinates sequential stages of sympathetic axon growth, innervation of targets, and survival in a manner dependent on the differential control of TRKA internalization, trafficking, and retrograde axonal signaling.
Neurotrophins (NTFs) act as survival and differentiation factors in the nervous system and have been detected in the developing rodent testis. To determine whether neurotrophins could influence development and maturation of the human fetal testis, Robinson et al. (2003) examined the cell-specific expression and distribution of several members of the neurotrophin family and their receptors during the second trimester, with particular emphasis on NT4 and TRKB. They detected expression of mRNA for NGF, NTF3 and NTF4 (162662), BDNF, the high-affinity receptors TRKA, TRKB, and TRKC, and the low-affinity p75 receptor (NGFR) in the human testis between 14 and 19 weeks' gestation. NT4 mRNA and protein were predominantly localized to the peritubular cells. These cells were also the site of expression of p75. By contrast, NGF and NT3 were mainly expressed in Sertoli and interstitial cells. The authors concluded that these data demonstrate the expression of neurotrophins and their receptors in the human fetal testis during the second trimester and indicate possible roles in the regulation of proliferation and survival of germ cells and peritubular cells.
Yoshimura et al. (2005) showed that GSK3-beta (605004) phosphorylated CRMP2 (602463) at thr514 and inactivated it. Expression of the nonphosphorylated form of CRMP2 or inhibition of GSK3-beta induced the formation of multiple axon-like neurites in hippocampal neurons. Expression of constitutively active GSK3-beta impaired neuronal polarization, whereas the nonphosphorylated form of CRMP2 counteracted the inhibitory effects of GSK3-beta, indicating that GSK3-beta regulates neuronal polarity through phosphorylation of CRMP2. Treatment of hippocampal neurons with neurotrophin-3 induced inactivation of GSK3-beta and dephosphorylation of CRMP2. Knockdown of CRMP2 inhibited NT3-induced axon outgrowth. These results suggested that NT3 decreases phosphorylated CRMP2 and increases nonphosphorylated active CRMP2, thereby promoting axon outgrowth.
Joo et al. (2014) showed that Trkc is required for dendritic growth and branching of mouse cerebellar Purkinje cells. Sparse Trkc knockout reduced dendrite complexity, but global Purkinje cell knockout had no effect. Removal of Nt3 from cerebellar granule cells, which provide major afferent input to developing Purkinje cell dendrites, rescued the dendrite defects caused by sparse Trkc disruption in Purkinje cells. Joo et al. (2014) concluded that NT3 from presynaptic neurons (granule cells) is required for TRKC-dependent competitive dendrite morphogenesis in postsynaptic neurons (Purkinje cells), a previously unknown mechanism of neural circuit development.
Crystal Structure
Gong et al. (2008) reported the 2.6-angstrom resolution crystal structure of NT3 complexed to the ectodomain of glycosylated p75(NTR) (162010). In contrast to the previously reported asymmetric complex structure, which contains a dimer of nerve growth factor (NGF; 162030) bound to a single ectodomain of deglycosylated p75(NTR), reported by He and Garcia (2004), Gong et al. (2008) showed that NT3 forms a central homodimer around which 2 glycosylated p75(NTR) molecules bind symmetrically. Symmetrical binding occurs along the NT3 interfaces, resulting in a 2:2 ligand-receptor cluster. A comparison of the symmetrical and asymmetric structures reveals significant differences in ligand-receptor interactions and p75(NTR) conformations. Biochemical experiments indicate that both NT3 and NGF bind to p75(NTR) with 2:2 stoichiometry in solution, whereas the 2:1 complexes are the result of artificial deglycosylation. Gong et al. (2008) therefore proposed that the symmetrical 2:2 complex reflects a native state of p75(NTR) activation at the cell surface. The authors concluded that their results provided a model for NTs/p75(NTR) recognition and signal generation, as well as insights into coordination between p75(NTR) and tyrosine kinase receptors.
Hattori et al. (1993) described a dinucleotide repeat polymorphism in the promoter region of the NTF3 gene.
Ernfors et al. (1994) generated NT3-deficient mice by gene targeting. Mutant mice displayed severe movement defects of the limbs, and most died shortly after birth. Substantial portions of peripheral sensory and sympathetic neurons were lost, whereas motor neurons were not affected. Spinal proprioceptive afferents and their peripheral sense organs (muscle spindles and Golgi tendon organs) were completely absent in homozygous mutant mice. The number of muscle spindles in heterozygous mutant mice was half of that in control mice, indicating that neurotrophin-3 is present at limiting concentrations in the embryo. Tessarollo et al. (1994) also studied the effects of inactivating the NT3 gene in embryonic stem cells by homologous recombination. The homozygous mutants failed to thrive and exhibited severe neurologic dysfunction.
Donovan et al. (1996) reported that Nt3 is essential in the mouse for the normal development of atria, ventricles, and cardiac outflow tracts. Previously unexplained perinatal lethality in mice homozygous for disruption of the gene was explained by the findings. Histologic and electrocardiographic analysis of homozygous deficient animals revealed severe cardiovascular abnormalities, including atrial and ventricular septal defects and tetralogy of Fallot, resembling some of the most common congenital malformations in humans. The observed defects were consistent with abnormalities in the survival and/or migration of cardiac neural crest early in embryogenesis and established an essential role for neurotrophin-3 in regulating the development of the mammalian heart.
Ma et al. (2002) found that ablation of Nt3 in mouse neocortex resulted in reduction of a set of axonal bundles projecting from thalamus through cortical white matter. These bundles included thalamocortical axons that normally establish connections with retrosplenial and visual cortex, sites of early postnatal Nt3 expression.
Cosgaya, J. M., Chan, J. R., Shooter, E. M. The neurotrophin receptor p75(NTR) as a positive modulator of myelination. Science 298: 1245-1248, 2002. [PubMed: 12424382] [Full Text: https://doi.org/10.1126/science.1076595]
Donovan, M. J., Hahn, R., Tessarollo, L., Hempstead, B. L. Identification of an essential nonneuronal function of neurotrophin 3 in mammalian cardiac development. Nature Genet. 14: 210-213, 1996. [PubMed: 8841198] [Full Text: https://doi.org/10.1038/ng1096-210]
Ernfors, P., Lee, K.-F., Kucera, J., Jaenisch, R. Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. Cell 77: 503-512, 1994. [PubMed: 7514502] [Full Text: https://doi.org/10.1016/0092-8674(94)90213-5]
Gong, Y., Cao, P., Yu, H., Jiang, T. Crystal structure of the neurotrophin-3 and p75(NTR) symmetrical complex. Nature 454: 789-793, 2008. [PubMed: 18596692] [Full Text: https://doi.org/10.1038/nature07089]
Hattori, M., Kuwata, S., Fukuda, R., Sasaki, T., Shibata, Y., Kazamatsuri, H., Nanko, S. Dinucleotide repeat polymorphism in the promoter region of neurotrophin-3 gene (NT3). Hum. Molec. Genet. 2: 1511 only, 1993. [PubMed: 8242090] [Full Text: https://doi.org/10.1093/hmg/2.9.1511-a]
He, X.-L., Garcia, K. C. Structure of nerve growth factor complexed with the shared neurotrophin receptor p75. Science 304: 870-875, 2004. [PubMed: 15131306] [Full Text: https://doi.org/10.1126/science.1095190]
Jones, K. R., Reichardt, L. F. Molecular cloning of a human gene that is a member of the nerve growth factor family. Proc. Nat. Acad. Sci. 87: 8060-8064, 1990. [PubMed: 2236018] [Full Text: https://doi.org/10.1073/pnas.87.20.8060]
Joo, W., Hippenmeyer, S., Luo, L. Dendrite morphogenesis depends on relative levels of NT-3/TrkC signaling. Science 346: 626-629, 2014. [PubMed: 25359972] [Full Text: https://doi.org/10.1126/science.1258996]
Kaisho, Y., Yoshimura, K., Nakahama, K. Cloning and expression of a cDNA encoding a novel human neurotrophic factor. FEBS Lett. 266: 187-191, 1990. [PubMed: 2365067] [Full Text: https://doi.org/10.1016/0014-5793(90)81536-w]
Kalcheim, C., Carmeli, C., Rosenthal, A. Neurotrophin 3 is a mitogen for cultured neural crest cells. Proc. Nat. Acad. Sci. 89: 1661-1665, 1992. [PubMed: 1542658] [Full Text: https://doi.org/10.1073/pnas.89.5.1661]
Kuruvilla, R., Zweifel, L. S., Glebova, N. O., Lonze, B. E., Valdez, G., Ye, H., Ginty, D. D. A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signaling. Cell 118: 243-255, 2004. [PubMed: 15260993] [Full Text: https://doi.org/10.1016/j.cell.2004.06.021]
Ma, L., Harada, T., Harada, C., Romero, M., Hebert, J. M., McConnell, S. K., Parada, L. F. Neurotrophin-3 is required for appropriate establishment of thalamocortical connections. Neuron 36: 623-634, 2002. [PubMed: 12441052] [Full Text: https://doi.org/10.1016/s0896-6273(02)01021-8]
Maisonpierre, P. C., Le Beau, M. M., Espinosa, R., III, Ip, N. Y., Belluscio, L., de la Monte, S. M., Squinto, S., Furth, M. E., Yancopoulos, G. D. Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations. Genomics 10: 558-568, 1991. [PubMed: 1889806] [Full Text: https://doi.org/10.1016/0888-7543(91)90436-i]
Ozcelik, T., Rosenthal, A., Francke, U. Chromosomal mapping of brain-derived neurotrophic factor and neurotrophin-3 genes in man and mouse. Genomics 10: 569-575, 1991. [PubMed: 1889807] [Full Text: https://doi.org/10.1016/0888-7543(91)90437-j]
Ramer, M. S., Priestley, J. V., McMahon, S. B. Functional regeneration of sensory axons into the adult spinal cord. Nature 403: 312-316, 2000. [PubMed: 10659850] [Full Text: https://doi.org/10.1038/35002084]
Robinson, L. L. L., Townsend, J., Anderson, R. A. The human fetal testis is a site of expression of neurotrophins and their receptors: regulation of the germ cell and peritubular cell population. J. Clin. Endocr. Metab. 88: 3943-3951, 2003. [PubMed: 12915691] [Full Text: https://doi.org/10.1210/jc.2003-030196]
Tessarollo, L., Vogel, K. S., Palko, M. E., Reid, S. W., Parada, L. F. Targeted mutation in the neurotrophin-3 gene results in loss of muscle sensory neurons. Proc. Nat. Acad. Sci. 91: 11844-11848, 1994. [PubMed: 7991545] [Full Text: https://doi.org/10.1073/pnas.91.25.11844]
Yoshimura, T., Kawano, Y., Arimura, N., Kawabata, S., Kikuchi, A., Kaibuchi, K. GSK-3-beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120: 137-149, 2005. [PubMed: 15652488] [Full Text: https://doi.org/10.1016/j.cell.2004.11.012]