Reduced activin A levels impair urogenital system development and compromise female mouse fertility

Activin A, encoded by the Inhba gene, is a versatile protein crucial for numerous biological processes, and its dysregulation is implicated in various human disorders. However, the perinatal lethality of Inhba knockout mice restricts the delineation of the full extent of this protein's function in the adult organism, particularly in reproduction. Here, we report the identification and characterization of a previously unrecognized InhbaLoxP/LoxP mouse line that exhibits a seven-fold reduction in activin A levels, establishing a novel hypomorphic Inhba model. Unlike the activin A knockout mice, the obtained InhbaLoxP/LoxP individuals survive to adulthood but exhibit impaired growth, as well as defects in hair and eye development. Notably, hypomorphic females display disrupted estrous cycles, elevated luteinizing hormone levels, and severe congenital malformations of the urogenital tract, which markedly compromise their fertility. These abnormalities arise from defective postnatal remodeling of the urogenital sinus, which normally regresses after birth to establish separate vaginal and urethral structures. Persistent urogenital sinus in adult hypomorphic females narrows the vaginal lumen, causes abnormal urethral insertion into the vaginal canal, and likely predisposes to pelvic organ prolapse, collectively preventing successful copulation. This unique mouse model thus uncovers a previously unrecognized, dosage-sensitive requirement for activin A in female reproductive development and anatomy. Overall, our findings highlight Inhba as a critical regulator of urogenital tract remodeling and identify this gene as a potential genetic component in rare human disorders such as persistent urogenital sinus and pelvic organ prolapse, paving the way for investigating the pathogenesis of these conditions.