P114. Sema4C-Plexin B2 signalling modulates ureteric branching in developing kidney

Abstract

Semaphorins, originally identified as axon guidance molecules, have recently been implicated in angiogenesis, function of the immune system and cancerous growth. Here we show that the deletion of Plexin B2 (Plxnb2), a semaphorin receptor that is expressed both in the pretubular aggregates and the tips of the ureteric buds in the developing kidney, results in renal hypoplasia and occasional double ureters. The rate of cell proliferation in ureteric epithelium and consequently the number of ureteric tips are reduced in the kidneys lacking Plexin B2 (Plxnb2−/−). Semaphorin 4C, a ligand for Plexin B2, stimulates branching of the ureteric epithelium in wild type and Plxnb2+/− kidney explants, but not in Plxnb2−/− explants. Isolated Plxnb2−/− ureteric buds fail to respond to branching induction by glial-cell-line-derived neurotrophic factor in vitro, but this response is rescued by either the presence of the metanephric mesenchyme or addition of Fibroblast growth factor 7 and Follistatin. The differentiation of the nephrogenic mesenchyme, its morphology and rate of apoptosis in the Plxnb2−/− kidneys are normal. Plexin B2 is co-expressed with Plexin B1 (Plxnb1). The deletion of Plxnb1 results in a transient embryonic phenotype with enhanced branching of the ureteric bud. The double homozygous Plxnb1−/− Plxnb2−/− mice show high embryonic lethality prior to onset of nephrogenesis. The only double homozygous embryo surviving to E12 showed hypoplastic kidneys with ureteric branches and diffentiating mesenchyme. Taken together, our results show that Sema4C-Plexin B2 signalling regulates ureteric branching and suggest non-redundant roles for Plexin B1 and Plexin B2 in kidney development.