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HGNC Approved Gene Symbol: NTRK3
Cytogenetic location: 15q25.3 Genomic coordinates (GRCh38): 15:87,859,751-88,256,739 (from NCBI)
For background information on the neurotrophic tyrosine receptor kinase (NTRK) family, see NTRK1 (191315).
Lamballe et al. (1991) isolated and characterized TRKC, a member of the TRK family of tyrosine protein kinase genes. They found that TRKC is preferentially expressed in the brain; in situ hybridization studies showed transcripts in the hippocampus, cerebral cortex, and the granular cell layer of the cerebellum. The product of the TRKC gene is a glycoprotein of 145 kD, gp145(trkC), which is equally related to the previously characterized gp140(trk) (TRKA) and gp145(trkB) (TRKB; 600456) tyrosine kinases. Lamballe et al. (1991) demonstrated that gp145(trkC) is a receptor for NTF3, a factor important in the development of certain areas of the central nervous system, but does not bind NGF or BDNF.
McGregor et al. (1994) cloned and sequenced the human TRKC cDNA and found that the predicted amino acid sequence is 97% and 98% homologous to the rat and porcine TRKC sequences, respectively. The rat Trkc had several isoforms due to alternative splicing in the tyrosine kinase domain. McGregor et al. (1994) cloned one human splice variant that had a nucleic acid sequence identical to the rat isoform with an insert of 14 amino acids.
Using in situ hybridization, Pinho et al. (2011) detected Trkc transcripts close to the Hensen node starting at stage 3 in chick embryos. Trkc expression expanded to the forming neural plate between stages 4 to 7, and thereafter Trkc was expressed throughout the neural plate except in the most caudal domains and in subregions of hindbrain.
Medulloblastoma, the most common malignant brain tumor of childhood, has a variable prognosis. Although half of the children and young adults with the disease survive longer than 10 years after diagnosis, the others relapse and die despite identical therapy. Segal et al. (1994) examined the expression of neurotrophins and their receptors in medulloblastoma samples snap-frozen in the operating room to preserve RNA integrity. All 12 tumors were found to express mRNA encoding neurotrophin-3 and its receptor TRKC. The level of TRKC expression was highly variable, with a more than 50-fold difference between the highest and lowest values. By Kaplan-Meier analysis, patients with tumors expressing high levels of TRKC mRNA had significantly longer intervals without disease progression than those with low levels and a more favorable overall survival. Thus, TRKC expression is a prognostic indicator for patients with medulloblastoma.
See ETV6 (600618) and Knezevich et al. (1998) for discussion of an ETV6-NTRK3 fusion gene involved in congenital (or infantile) fibrosarcoma (CFS).
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 activity. Moreover, the enhancement of myelin formation by endogenous BDNF (113505) is mediated by the p75(NTR) receptor, whereas TRKC receptors are responsible for neurotrophin-3 (NT3; 162660) 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.
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 nerve growth factor (NGF; 162030), NTF3 and NTF4, BDNF, the high-affinity receptors TRKA (191315), TRKB, and TRKC, and the low-affinity p75 receptor (NGFR; 162010) 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.
Laneve et al. (2007) identified the mRNA encoding a truncated isoform of NTRK3 (t-NTRK3) lacking the kinase domain as the target of 3 microRNAs (miRNAs), MIRN9 (see 611186), MIRN125A (611191), and MIRN125B (see 610104), that were upregulated in a human neuroblastoma cell line by retinoic acid. The 3-prime UTR of the t-NTRK3 transcript has a binding site for MIRN9 and another for both MIRN125A and MIRN125B, which share the same seed sequence. These miRNAs repressed t-NTRK3 expression in an additive manner, and downregulation of t-NTRK3 was critical for regulating neuroblastoma cell growth. Consistent with their function, MIRN9, MIRN125A, and MIRN125B were downmodulated in primary neuroblastoma tumors.
By functional studies in HeLa cells, Muinos-Gimeno et al. (2009) demonstrated that 5 miRNAs regulate the truncated form of NTRK3. MIRN485-3p decreased activity by 17%, whereas MIRN509 and MIRN625 caused a striking reduction of more than 50% in luciferase activity, indicating strong repression. MIRN128 (611774) and MIRN765 showed intermediate repressive activity.
Using engineered embryonic stem cells, Nikoletopoulou et al. (2010) demonstrated that the neurotrophin receptors TRKA and TRKC instruct developing neurons to die, both in vitro and in vivo. By contrast, TRKB (600456), a closely related receptor primarily expression in the central nervous system, does not. These results indicated that TRKA and TRKC behave as dependence receptors, explaining why developing sympathetic and sensory neurons become trophic factor-dependent for survival. Nikoletopoulou et al. (2010) suggested that the expansion of the TRK gene family that accompanied the segregation of the peripheral from the central nervous system generated a novel mechanism of cell number control.
Using a time-course study, Pinho et al. (2011) identified Trkc as an early-response gene to neural-inducing signals from the organizer, the Hensen node, in chick embryos.
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 neurotrophin-3 (NT3; 162660) 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.
By PCR analysis of a somatic cell hybrid panel and by fluorescence in situ hybridization with the cDNA clone, McGregor et al. (1994) mapped the NTRK3 gene to chromosome 15q24-q25.
Valent et al. (1997) confirmed the assignment of NTRK3 to chromosome 15q25 by fluorescence in situ hybridization.
Susceptibility to Anxiety Disorders
Muinos-Gimeno et al. (2009) identified 4 SNPs in the 3-prime untranslated region of the truncated isoform of NTRK3 that were within MIRN target sites. Analysis of 212 patients with panic disorder (see 607834), 153 patients with obsessive-compulsive disorder (164230), and 324 controls showed that 2 SNPs were common variants ({dbSNP ss102661463} and rs28521337). The other 2 SNPs were rare, each identified only in 1 chromosome of a patient with panic disorder: a T-to-C change ({dbSNP ss102661458}), in the target sites of MIRN128 and MIRN509, and a G-to-C change ({dbSNP ss102661460}), in the target site of MIRN765. Both patients were male and had the agoraphobic phenotype. Functional studies showed that the C alleles of both SNPs resulted in modest but significant recovery of luciferase activity (10 to 15%) when expressed with their corresponding MIRNs compared to the wildtype alleles. In another study, the common C-to-G SNP rs28521337, located in the binding site for MIRN485-3p, showed a significant association with the hoarding subtype of obsessive-compulsive disorder (odds ratio of 0.53, p = 0.0048 after Bonferroni correction). The findings suggested that the C allele of this SNP could have a moderate protective effect against the hoarding phenotype. However, functional studies showed no significant change in luciferase levels for the G compared to the C allele (92% versus 85%), indicating that the variant does not interfere significantly with MIRN binding. Muinos-Gimeno et al. (2009) suggested that functional variation in expression of the NTRK3 gene may influence susceptibility to the development of anxiety disorders.
Susceptibility to Ventricular Septal Defects
In 467 patients with heart defects, Werner et al. (2014) identified 4 missense mutations in the NTRK3 gene in 4 patients with ventricular septal defects (VSDs). The mutations, which were not found in ethnically matched controls, were predicted to be deleterious. Functional analysis using neuroblastoma cell lines expressing mutant TrkC demonstrated that 1 of the mutations significantly reduced autophosphorylation of TrkC in response to ligand binding, subsequently decreasing phosphorylation of downstream target proteins. In addition, compared with wildtype, 3 of the 4 cell lines expressing mutant TrkC showed altered cell growth in low-serum conditions without supplemental neurotrophin-3 (NTF3; 162660). Werner et al. (2014) concluded that their findings suggested a novel pathophysiologic mechanism involving NTRK3 in the development of VSDs.
Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including NTRK3, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development.
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]
Dorus, S., Vallender, E. J., Evans, P. D., Anderson, J. R., Gilbert, S. L., Mahowald, M., Wyckoff, G. J., Malcom, C. M., Lahn, B. T. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119: 1027-1040, 2004. [PubMed: 15620360] [Full Text: https://doi.org/10.1016/j.cell.2004.11.040]
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]
Knezevich, S. R., McFadden, D. E., Tao, W., Lim, J. F., Sorensen, P. H. B. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nature Genet. 18: 184-187, 1998. [PubMed: 9462753] [Full Text: https://doi.org/10.1038/ng0298-184]
Lamballe, F., Klein, R., Barbacid, M. TRKC, a new member of the TRK family of tyrosine protein kinases, is a receptor for neurotrophin-3. Cell 66: 967-979, 1991. [PubMed: 1653651] [Full Text: https://doi.org/10.1016/0092-8674(91)90442-2]
Laneve, P., Di Marcotullio, L., Gioia, U., Fiori, M. E., Ferretti, E., Gulino, A., Bozzoni, I., Caffarelli, E. The interplay between microRNAs and the neurotrophin receptor tropomyosin-related kinase C controls proliferation of human neuroblastoma cells. Proc. Nat. Acad. Sci. 104: 7957-7962, 2007. [PubMed: 17483472] [Full Text: https://doi.org/10.1073/pnas.0700071104]
McGregor, L. M., Baylin, S. B., Griffin, C. A., Hawkins, A. L., Nelkin, B. D. Molecular cloning of the cDNA for human TrkC (NTRK3), chromosomal assignment, and evidence for a splice variant. Genomics 22: 267-272, 1994. [PubMed: 7806211] [Full Text: https://doi.org/10.1006/geno.1994.1383]
Muinos-Gimeno, M., Guidi, M., Kagerbauer, B., Martin-Santos, R., Navines, R., Alonso, P., Menchon, J. M., Gratacos, M., Estivill, X., Espinosa-Parrilla, Y. Allele variants in functional microRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders. Hum. Mutat. 30: 1062-1071, 2009. [PubMed: 19370765] [Full Text: https://doi.org/10.1002/humu.21005]
Nikoletopoulou, V., Lickert, H., Frade, J. M., Rencurel, C., Giallonardo, P., Zhang, L., Bibel, M., Barde, Y.-A. Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not. Nature 467: 59-63, 2010. [PubMed: 20811452] [Full Text: https://doi.org/10.1038/nature09336]
Pinho, S., Simonsson, P. R., Trevers, K. E., Stower, M. J., Sherlock, W. T., Khan, M., Streit, A., Sheng, G., Stern, C. D. Distinct steps of neural induction revealed by Asterix, Obelix and TrkC, genes induced by different signals from the organizer. PLoS One 6: e19157, 2011. Note: Electronic Article. [PubMed: 21559472] [Full Text: https://doi.org/10.1371/journal.pone.0019157]
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]
Segal, R. A., Goumnerova, L. C., Kwon, Y. K., Stiles, C. D., Pomeroy, S. L. Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma. Proc. Nat. Acad. Sci. 91: 12867-12871, 1994. [PubMed: 7809137] [Full Text: https://doi.org/10.1073/pnas.91.26.12867]
Valent, A., Danglot, G., Bernheim, A. Mapping of the tyrosine kinase receptors trkA (NTRK1), trkB (NTRK2) and trkC (NTRK3) to human chromosomes 1q22, 9q22 and 15q25 by fluorescence in situ hybridization. Europ. J. Hum. Genet. 5: 102-104, 1997. [PubMed: 9195161]
Werner, P., Paluru, P., Simpson, A. M., Latney, B., Iyer, R., Brodeur, G. M., Goldmuntz, E. Mutations in NTRK3 suggest a novel signaling pathway in human congenital heart disease. Hum. Mutat. 35: 1459-1468, 2014. [PubMed: 25196463] [Full Text: https://doi.org/10.1002/humu.22688]