Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice.
The receptor tyrosine kinase ret protooncogene (RET) is implicated in the pathogenesis of several diseases and in several developmental defects, particularly those in neural crest-derived structures and the genitourinary system. In order to further elucidate RET-mediated mechanisms that contribute to these diseases and decipher the basis for specificity in the pleiotropic effects of RET, we characterized development of the enteric and autonomic nervous systems in mice expressing RET9 or RET51 isoforms harboring mutations in tyrosine residues that act as docking sites for the adaptors Plcgamma, Src, Shc, and Grb2. Using this approach, we found that development of the genitourinary system and the enteric and autonomic nervous systems is dependent on distinct RET-stimulated signaling pathways. Thus, mutation of RET51 at Y1062, a docking site for multiple adaptor proteins including Shc, caused distal colon aganglionosis reminiscent of Hirschsprung disease (HSCR). On the other hand, this mutation in RET9, which encodes an isoform that lacks the Grb2 docking site present in RET51, produced severe abnormalities in multiple organs. Mutations that abrogate RET-Plcgamma binding, previously shown to produce features reminiscent of congenital anomalies of kidneys or urinary tract (CAKUT) syndrome, produced only minor abnormalities in the nervous system. Abrogating RET51-Src binding produced no major defects in these systems. These studies provide insight into the basis of organotypic specificity and redundancy in RET signaling within these unique systems and in diseases such as HSCR and CAKUT.
Jain
Sanjay
S
Department of Internal Medicine (Renal Division), Washington University School of Medicine, St. Louis, Missouri 63110, USA. sjain22@wustl.edu
Knoten
Amanda
A
Hoshi
Masato
M
Wang
Hongtao
H
Vohra
Bhupinder
B
Heuckeroth
Robert O
RO
Milbrandt
Jeffrey
J
D000818:Animals; D001341:Autonomic Nervous System / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism; D006627:Hirschsprung Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000002:abnormalities* / Q000196:embryology; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009432:Neural Crest / Q000002:abnormalities*; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
D051380:GRB2 Adaptor Protein; C495950:Grb2 protein, rat; D007527:Isoenzymes; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse; D016392:Proto-Oncogene Proteins pp60(c-src); D051966:Phospholipase C gamma