Rac1 restrains actomyosin to enable ciliogenesis and mechanosensing in the postnatal kidney

Multicystic dysplastic kidney (MCDK) is a severe congenital malformation of unknown cause that is fatal when it affects both kidneys. Rare familial variants associated with congenital anomalies of the kidney and urinary tract (CAKUT) that alter Rho GTPase signaling were recently identified in children with MCDK. Here, we show that mice lacking the Rho GTPase Rac1 in the developing nephron die within weeks of birth from MCDK. This phenotype occurs because Rac1 supports postnatal proximal tubule maturation by coordinating actomyosin regulation, primary cilia formation, and fluid shear stress sensing. Rac1 controls ciliogenesis by restricting GEF-H1–dependent actomyosin contractility, and this pathway promotes apical clearing of the actin cytoskeleton to facilitate ciliogenesis. Pharmacological myosin inhibition restores ciliogenesis and flow-induced differentiation in cells and attenuates cystic-dysplastic remodeling in Rac1 mutant mice. We conclude that Rac1 links postnatal mechanical signals from urine flow to cellular differentiation in the growing kidney, a pathway amenable to therapeutic cytoskeletal targeting.