Alternative titles; symbols
HGNC Approved Gene Symbol: GFRA2
Cytogenetic location: 8p21.3 Genomic coordinates (GRCh38): 8:21,690,398-21,812,345 (from NCBI)
In an effort to identify mediators of glial cell line-derived neurotrophic factor (GDNF; 600837), a potent survival factor for several populations of neurons, Suvanto et al. (1997) cloned the human and rat cDNA sequences of GDNFR-beta, a gene encoding a 464-amino acid homolog of GDNFR-alpha (601496). Similarly to GDNFR-alpha, GDNFR-beta mediates GDNF-induced RET (164761) autophosphorylation in transfected cells. By Northern hybridization, Suvanto et al. (1997) showed that the transcript level of human GDNFR-beta mRNA is high in the adult brain, intestine, and placenta, and in fetal brain, lung, and kidney. By in situ hybridization, they demonstrated that GDNFRB mRNA shows in the rat embryo a different distribution to that of GDNFRA mRNA, especially in adrenal gland, kidney, and gut. In the developing nervous system, GDNFRB mRNA expression was restricted to certain neuronal populations, while GDNFRA mRNA was widely expressed also in nonneuronal cells. Distinct tissue distribution of GDNFRB mRNA and its ability to mediate GDNF signal in transfected cells suggested a role in signal transduction of GDNF and, possibly, related neurotrophic factors in vivo.
Baloh et al. (1997) independently described the cloning and initial characterization of a second coreceptor for both neurturin (NRTN; 602018) and GDNF signaling. To name the receptors appropriately for their ability to function in both GDNF and NRTN signaling, the authors referred to them as TGF-beta-related neurotrophic factor receptors 1 and 2 (TrnR1 and TmR2), where TmR1 corresponds to GDNFR-alpha.
See also the reports by Klein et al. (1997) and Sanicola et al. (1997). Various nomenclature systems have been used to describe this gene.
Vanhorne et al. (2001) cloned the human GFRA2 locus, characterized the gene structure, and compared it with other GFRA family members.
Vanhorne et al. (2001) determined that the GFRA2 gene has 9 coding exons that are similar in size and organization to those of other GFRA family genes.
By fluorescence in situ hybridization, Suvanto et al. (1997) assigned the GDNFRB gene to chromosome 8p22-p21. They assigned the mouse Gdnfrb gene to chromosome 14D3-E1.
By fluorescence in situ hybridization, Baloh et al. (1997) mapped the GDNFRB gene to 8p21-p12; 8p21 is a consensus assignment.
Vanhorne et al. (2001) performed a mutation screen of the GFRA2 gene in a panel of patients with Hirschsprung disease (142623). Although some sequence variants were found, there was no difference in frequency of these between control and HSCR populations. Thus, although GFRA2 is required for the development of the myenteric nerve plexus, no indication of involvement in the causation of Hirschsprung disease could be found.
In Gfra2-null mice, Rossi et al. (2003) found that the density of substance P (see 162320)-containing myenteric ganglion cells and nerve bundles was significantly reduced, and the transit of test material through small intestine was 25% slower compared to wildtype mice. The knockout mice had approximately 80% fewer intrapancreatic neurons, severely impaired cholinergic innervation of the exocrine but not the endocrine pancreas, and increased fecal fat content. Vagally mediated stimulation of pancreatic secretion in vivo was virtually abolished. The Grfa2-null mice had retarded growth accompanied by reduced fat mass and an elevated basal metabolic rate. The knockout mice also drank more water than wildtype controls, and wet-mash feeding resulted in partial growth rescue. Rossi et al. (2003) suggested that the growth retardation in mice lacking Gfra2 is largely due to impaired salivary and pancreatic secretion and intestinal dysmotility.
Baloh, R. H., Tansey, M. G., Golden, J. P., Creedon, D. J., Heuckeroth, R. O., Keck, C. L., Zimonjic, D. B., Popescu, N. C., Johnson, E. M., Jr., Milbrandt, J. TrnR2, a novel receptor that mediates neurturin and GDNF signaling through Ret. Neuron 18: 793-802, 1997. [PubMed: 9182803] [Full Text: https://doi.org/10.1016/s0896-6273(00)80318-9]
Klein, R. D., Sherman, D., Ho, W.-H., Stone, D., Bennett, G. L., Moffat, B., Vandlen, R., Simmons, L., Gu, Q., Hongo, J.-A., Devaux, B., Poulsen, K., Armanini, M., Nozaki, C., Asai, N., Goddard, A., Phillips, H., Henderson, C. E., Takahashi, M., Rosenthal, A. A GPI-linked protein that interacts with Ret to form a candidate neurturin receptor. Nature 387: 717-721, 1997. Note: Erratum: Nature 392: 210 only, 1998. [PubMed: 9192898] [Full Text: https://doi.org/10.1038/42722]
Rossi, J., Herzig, K.-H., Voikar, V., Hiltunen, P. H., Segerstrale, M., Airaksinen, M. S. Alimentary tract innervation deficits and dysfunction in mice lacking GDNF family receptor alpha-2. J. Clin. Invest. 112: 707-716, 2003. [PubMed: 12952919] [Full Text: https://doi.org/10.1172/JCI17995]
Sanicola, M., Hession, C., Worley, D., Carmillo, P., Ehrenfels, C., Walus, L., Robinson, S., Jaworski, G., Wei, H., Tizard, R., Whitty, A., Pepinsky, R. B., Cate, R. L. Glial cell line-derived neurotrophic factor-dependent RET activation can be mediated by two different cell-surface accessory proteins. Proc. Nat. Acad. Sci. 94: 6238-6243, 1997. [PubMed: 9177201] [Full Text: https://doi.org/10.1073/pnas.94.12.6238]
Suvanto, P., Wartiovaara, K., Lindahl, M., Arumae, U., Moshnyakov, M., Horelli-Kuitunen, N., Airaksinen, M. S., Palotie, A., Sariola, H., Saarma, M. Cloning, mRNA distribution and chromosomal localisation of the gene for glial cell lined-derived neurotrophic factor receptor beta, a homologue to GDNFR-alpha. Hum. Molec. Genet. 6: 1267-1273, 1997. [PubMed: 9259272] [Full Text: https://doi.org/10.1093/hmg/6.8.1267]
Vanhorne, J. B., Gimm, O., Myers, S. M., Kaushik, A., von Deimling, A., Eng, C., Mulligan, L. M. Cloning and characterization of the human GFRA2 locus and investigation of the gene in Hirschsprung disease. Hum. Genet. 108: 409-415, 2001. [PubMed: 11409869] [Full Text: https://doi.org/10.1007/s004390100506]