Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret

Abstract

Receptor tyrosine kinases (RTKs) are cell-surface molecules that transduce signals for cell growth and differentiation. The RTK encoded by the c-ret proto-oncogene is rearranged and constitutively activated in a large proportion of thyroid papillary carcinomas, and germ-line point mutations in c-ret seem to be responsible for the dominantly inherited cancer syndromes multiple endocrine neoplasia (MEN) types 2A and B. The gene is expressed in the developing central and peripheral nervous systems (sensory, autonomic and enteric ganglia) and the excretory system (Wolffian duct and ureteric bud epithelium) of mice, indicating that it may play a role in normal development. Here we show that mice homozygous for a targeted mutation in c-ret develop to term, but die soon after birth, showing renal agenesis or severe dysgenesis, and lacking enteric neurons throughout the digestive tract. Ret is thus an essential component of a signalling pathway required for renal organogenesis and enteric neurogenesis.

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

“…The crucial requirement for Ret in enteric nervous system development is underscored by disorders such as HSCR, in which Ret loss of function leads to almost complete absence of enteric innervation in varying lengths of the distal gut (Schuchardt et al , 1994; Sasselli et al , 2012). Whilst the contribution of enteric aganglionosis to HSCR is unquestionable, our findings raise the possibility that, if the epithelial expression of Ret is conserved in humans, dysregulation of epithelial signalling may contribute to disorders that, like HSCR, result from Ret mutation.…”

“…It is now well established that the endogenous activity of Ret is required for the formation and/or maintenance of a variety of cell types including neuronal, kidney, lymphoid, hematopoietic and testis germ cells (Schuchardt et al , 1994; Naughton et al , 2006; Veiga‐Fernandes et al , 2007; Ibanez, 2013; Fonseca‐Pereira et al , 2014). In these cells, Ret signalling is involved in a diverse range of developmental processes including proliferation, migration survival and/or differentiation (Sasselli et al , 2012; Ibanez, 2013).…”

Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

“…Consistently, RETde®cient mice show lack of enteric neurons and renal dysgenesis (Schuchardt et al, 1994), and`loss of function' RET mutations are associated with Hirschsprung's disease Edery et al, 1994;Pasini et al, 1995;Carlomagno et al, 1996), which is characterized by the congenital defect of intestinal innervation. Recently, GDNF (glial cell line derived neurotrophic factor) has been identi®ed as one functional ligand for Ret.…”

Genomic structure and chromosomal localization of the human GDNFR-α gene

“…RET activation plays a major role in growth survival and/or di erentiation of neural crest derivatives and also in induction of the metanephric kidney. Consistent with this, RET-/-and GDNF-/-mice lack enteric ganglia and have dysgenic or agenic kidneys (Schuchardt et al, 1994;Moore et al, 1996;Pichel et al, 1996;Sa nchez et al, 1996). Thus, GDNFR-a, as a member of the RET ligand complex, is also predicted to contribute to these developmental processes.…”