Hedgehog-dependent and Hedgehog-independent roles for Growth Arrest Specific 1 in mammalian kidney morphogenesis

Growth arrest specific 1 (GAS1) is a key regulator of mammalian embryogenesis, best known for its role in Hedgehog (HH) signaling, but with additional described roles in the FGF, RET, and NOTCH pathways. Previous work indicated a later role for GAS1 in kidney development through FGF pathway modulation. Here, we demonstrate that GAS1 is essential for both mesonephrogenesis and metanephrogenesis– most notably, Gas1 deletion in mice results in renal agenesis in a genetic background-dependent fashion. Mechanistically, GAS1 promotes mesonephrogenesis in a HH-dependent fashion, performing a unique co-receptor function, while promoting metanephrogenesis in a HH-independent fashion, acting as a putative secreted RET co-receptor. Our data indicate that Gas1 deletion leads to renal agenesis through a transient reduction in metanephric mesenchyme proliferation– a phenotype that can be rescued by exogenous RET pathway stimulation. Overall, this study indicates that GAS1 contributes to early kidney development through the integration of multiple different signaling pathways.