13-P066 SPROUTY1 and RTK signaling in kidney development

as axon guidance cues. Both plexin B1 and plexin B2 are expressed during mouse kidney development. Inbred plexin B2 knockout (PB2 KO) mice die prenatally with defects in olfactory bulb development, neuronal proliferation and neural tube closure (exencephaly). We report here that these PB2 KO mice have defects also in kidney morphogenesis. In PB2 / embryos the kidneys are smaller and the number of ureteric branches is decreased compared to the PB2+/ and wild type (WT) littermates. Occasionally also unilateral double kidneys were seen. In vitro, the ligand of plexin B2, Sema4C, increased the number of ureteric branches in both PB2 +/ and WT kidneys. The stimulatory effect of Sema4C on ureteric branching was more pronounced in the PB2+/ than in WT kidneys, increasing the number of tips by approximately 50%. In the PB2+/ kidneys Sema4C induced ectopic budding of the Wolffian duct. Also the glial cell line derived neurotrophic factor GDNF was able to induce formation of ectopic ureteric buds in PB2 / , +/ and WT Wolffian ducts. However, GDNF alone had minimal effect on the branching of separated PB2 / ureteric buds grown in vitro in three-dimensional Matrigel culture, whereas it was able to potentiate branching morphogenesis induced by fibroblast growth factor 7 (FGF7) and follistatin. The expression patterns of GDNF, related receptors (Ret, GFRa-1, Met) and their downstream regulator Sprouty1 were normal in PB2 / kidneys. Our results show that Sema4C–plexin B2-signalling modulates the morphogenesis of the ureteric epithelium.