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The GDNF family members (GDNF, neurturin and persephin) signal through multicomponent receptors that consist of the Ret receptor tyrosine kinase and one of four glycosyl-phosphatidylinositol (GPI)-linked ligand-binding subunits (GFR alpha-1 -4). GFR alpha-1, -2, and -4 are the preferred ligand-binding subunits for GDNF, neurturin and persephin, respectively. The Ret tyrosine-kinase receptor is encoded by the c-ret proto-oncogene. Human and mouse Ret share 83% amino acid sequence homology.
Mutations in this gene are associated with the disorders multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, Hirschsprung disease, and medullary thyroid carcinoma. Two transcript variants encoding different isoforms have been found for this gene.
Image: Ret staining of spermatagonial stem cells
Images: Testosterone and Mullerian inhibiting substance (MIS) do not have deleterious effects on enteric nervous system (ENS) precursor proliferation, differentiation, or survival. A-D: Cultured immunoselected embryonic day (E) 12.5 C57BL/6 ENS precursors were grown for 24 hr with or without glial cell line-derived neurotrophic factor (GDNF), testosterone, or MIS. A-C: Triple-label immunohistochemistry was performed with antibodies to Ret (A), neuron-specific beta III tubulin (TuJ1; B), or histone 3 phosphate (H3P; C). D: Shows the merged image. Arrowheads show a Ret+ TuJ1+ H3P- cell. Arrows identify a cell with a punctate nuclear staining pattern characteristic of H3P immunohistochemistry. Both TuJ1 and H3P antibodies were generated in rabbits, but easily were distinguished based on characteristic staining patterns. E,H: Quantitative analysis of TuJ1 immunoreactivity in Ret+ cells shows that treatment with testosterone or MIS does not alter expression of the neuronal differentiation marker recognized by TuJ1 in the presence or absence of GDNF. F,I: Quantitative analysis of proliferation (H3P+ cells) shows that neither testosterone nor MIS influences proliferation of Ret+TuJ1+ cells in the presence or absence of GDNF. G,J: Quantitative analysis of proliferating Ret+TuJ1- cell demonstrates increased proliferation in response to testosterone, but not MIS in the absence of GDNF. There was no additive effect of testosterone plus GDNF under these conditions. Asterisks indicate P < 0.05 vs. control. N = 3 experiments; greater than 1,350 cells/experiment were analyzed for each condition. Scale bar = 50 um.