Lineage-specific roles of hedgehog-GLI signaling during mammalian kidney development.

Aberrant hedgehog (Hh) signaling during embryogenesis results in various severe congenital abnormalities, including renal malformations. The molecular mechanisms that underlie congenital renal malformations remain poorly understood. Here, we review the current understanding of the lineage-specific roles of Hh signaling during renal morphogenesis and how aberrant Hh signaling during embryonic kidney development contributes to renal malformation.

Hedgehog-GLI signaling in Foxd1-positive stromal cells promotes murine nephrogenesis via TGFß signaling.

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 (Smo-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 TGFß2 signaling in Smo-deficient mutants. We show that neutralization and knockdown of TGFß2 in explants inhibited nephrogenesis. In addition, we demonstrate that concurrent deletion of Tgfbr2 in stromal and nephrogenic cells in vivo results in decreased nephron formation and an expanded nephrogenic precursor domain similar to that observed in Smo-deficient mutant mice. Together, our data suggest a mechanism whereby a stromal hedgehog-TGFß2 signaling axis acts to control nephrogenesis.