Rac1 in nephron progenitor cells is essential for kidney development.

Renal hypoplasia is a common congenital condition characterized by abnormally small kidneys with a reduced number of nephrons. During embryonic development, nephron formation relies on repetitive interactions between nephron progenitor cells (NPCs) and surrounding epithelial and stromal tissue, a process tightly regulated by genetic factors. NPCs are crucial to kidney development due to their self-renewal and multipotent abilities. Rac1 is a small GTPase and its mutation is implicated in multiple events of development and disease. While aberrant Rac1 activity has been linked to various kidney diseases, its role in NPCs remains unclear. In this study, we generated tissue-specific Rac1 knockout models in NPCs. Our data demonstrate that Rac1 deficiency disrupts cell cycle progression and reduces cell proliferation rates. Consequently, Rac1 conditional knockout kidneys exhibit fewer NPCs and nascent nephrons, resulting in a hypoplastic phenotype. Using qPCR and immunostaining, we further show that JNK signaling activity is downregulated in both Rac1-deficient NPCs and in vivo models. Conversely, expression of an autoactivated form of Rac1 (Rac1) in NPCs increases NPC numbers per ureteric bud and enhances cell proliferation, accompanied by upregulated JNK signaling. We conclude that Rac1 plays a critical role in maintaining NPC proliferation and self-renewal, likely through the JNK signaling pathway.