Sprouty1 Is a Critical Regulator of GDNF/RET-Mediated Kidney Induction

Abstract

Intercellular signaling molecules and their receptors, whose expression must be tightly regulated in time and space, coordinate organogenesis. Regulators of intracellular signaling pathways provide an additional level of control. Here we report that loss of the receptor tyrosine kinase (RTK) antagonist, Sprouty1 (Spry1), causes defects in kidney development in mice. Spry1(-/-) embryos have supernumerary ureteric buds, resulting in the development of multiple ureters and multiplex kidneys. These defects are due to increased sensitivity of the Wolffian duct to GDNF/RET signaling, and reducing Gdnf gene dosage correspondingly rescues the Spry1 null phenotype. We conclude that the function of Spry1 is to modulate GDNF/RET signaling in the Wolffian duct, ensuring that kidney induction is restricted to a single site. These results demonstrate the importance of negative feedback regulation of RTK signaling during kidney induction and suggest that failures in feedback control may underlie some human congenital kidney malformations.

Sprouty2 inhibits BDNF-induced signaling and modulates neuronal differentiation and survival

“…22 In the embryonic kidney or the lung, Spry proteins play key roles during branching morphogenesis processes. 12 Likewise, expression of Spry in a feedback loop may allow the right dose of signaling required for appropriate neurite growth and branching.…”

“…Mammalian spry genes are expressed in highly restricted patterns in the embryo during development and in many adult tissues. They were shown to play important roles in the development of various organs, including lung, 10 kidney, 11,12 tooth 13 and testis. 14 At the cellular level, overexpression of Spry proteins antagonizes proliferation, migration and differentiation in response to serum or growth factors in various cell lines.…”

GDNF/Ret signaling and the development of the kidney

“…2d-f). (49) Instead, Sprouty1 appears to regulate the response to GDNF. While in other developing organs such as the lung, Sprouty proteins regulate the response to FGFs, (50) the urogenital defects in Sprouty1 À/À embryos seem to be caused by a failure to regulate the GDNF pathway, because they can be rescued by reducing the GDNF gene dosage.…”

Sprouty4 negatively regulates protein kinase C activation by inhibiting phosphatidylinositol 4,5-biphosphate hydrolysis

“…T Ayada et al bud-derived epithelial tubes (Basson et al, 2005(Basson et al, , 2006, mSprouty2 regulates embryonic lung branching morphogenesis (Tefft et al, 1999) as well as motor nerve networks in digestive organs (Taketomi et al, 2005). Angiogenesis is another form of branching morphogenesis and the overexpression of mSprouty4 has been shown to inhibit branching and sprouting of small vessels (Lee et al, 2001).…”