Shroom3 and Kidney Development

Abstract

The average human kidney contains approximately one million nephrons, which are established at birth. Nephrons arise from nephron progenitor cells, a dynamic cell population that requires a delicate balance between proliferation and differentiation during kidney development. Disruptions in this balance result in reduced nephron numbers, which greatly increases susceptibility to kidney dysfunction. Studies have associated genetic variants in SHROOM3 with renal aplasia and kidney dysfunction. SHROOM3 is a cytoskeletal regulator that is highly expressed in nephron progenitors, suggesting a role in nephron development. My objective was to investigate whether SHROOM3 deficiency in nephron progenitors specifically affects nephron formation and predisposes to kidney dysfunction. SHROOM3 mutant mice exhibited perinatal lethality with severe bilateral renal hypodysplasia. The phenotype emerged between embryonic day (E) 12.5 and E15.5, with progressive depletion of proliferating Six2+ progenitors beginning at E14.5 and complete loss by E15.5. WT1 staining confirmed that, by E15.5, nephron progenitors were absent, and only differentiated glomerular structures remained. Some mutants survived to adulthood without renal hypodysplasia but had significantly reduced kidney mass compared to the wild type, as well as kidney dysfunction characterized by increased serum creatinine, elevated urea, and proteinuria. These findings demonstrate that SHROOM3 deficiency does not impair glomerular maturation but instead leads to premature exhaustion of the progenitor pool, reducing overall nephron endowment. In severe cases, this lower nephron number results in renal aplasia, while in milder cases, nephron deficits predispose to adult-onset kidney dysfunction. These studies highlight SHROOM3 as a critical regulator of early nephron development, with implications for both congenital and progressive kidney disorders.