Hedgehog-GLI signaling in<i>Foxd1-</i>positive stromal cells promotes nephrogenesis Via TGFβ signaling

Abstract

Normal kidney function depends on the proper development of the nephron: the functional unit of the kidney. Reciprocal signaling interactions between the stroma and nephron progenitor compartment have been proposed to control nephron development. Here, we show that removal of hedgehog intracellular effector smoothened (<i>Smo</i>-deficient mutants) in the cortical stroma results in an abnormal renal capsule, and an expanded nephron progenitor domain with an accompanying decrease in nephron number via a block in epithelialization. We show that stromal-hedgehog-Smo signaling acts through a GLI3 repressor. Whole-kidney RNA sequencing and analysis of FACS-isolated stromal cells identified impaired TGFβ2 signaling in <i>Smo</i>-deficient mutants. We show that neutralization and knockdown of TGFβ2 in explants inhibited nephrogenesis. In addition, we demonstrate that concurrent deletion of <i>Tgfbr2</i> in stromal and nephrogenic cells <i>in vivo</i> results in decreased nephron formation and an expanded nephrogenic precursor domain similar to that observed in <i>Smo</i>-deficient mutant mice. Together, our data suggest a mechanism whereby a stromal hedgehog-TGFβ2 signaling axis acts to control nephrogenesis.