Suppression of Sertoli cell tumour development during the first wave of spermatogenesis in inhibin α-deficient mice.

A dynamic partnership between follicle-stimulating hormone (FSH) and activin is required for normal Sertoli cell development and fertility. Disruptions to this partnership trigger Sertoli cells to deviate from their normal developmental pathway, as observed in inhibin α-knockout (Inha-KO) mice, which feature Sertoli cell tumours in adulthood. Here, we identified the developmental windows by which adult Sertoli cell tumourigenesis is most FSH sensitive. FSH was suppressed for 7 days in Inha-KO mice and wild-type littermates during the 1st, 2nd or 4th week after birth and culled in the 5th week to assess the effect on adult Sertoli cell development. Tumour growth was profoundly reduced in adult Inha-KO mice in response to FSH suppression during Weeks 1 and 2, but not Week 4. Proliferative Sertoli cells were markedly reduced in adult Inha-KO mice following FSH suppression during Weeks 1, 2 or 4, resulting in levels similar to those in wild-type mice, with greatest effect observed at the 2 week time point. Apoptotic Sertoli cells increased in adult Inha-KO mice after FSH suppression during Week 4. In conclusion, acute FSH suppression during the 1st or 2nd week after birth in Inha-KO mice profoundly suppresses Sertoli cell tumour progression, probably by inhibiting proliferation in the adult, with early postnatal Sertoli cells being most sensitive to FSH action.

Activin signaling regulates Sertoli cell differentiation and function.

Throughout development, activin A signaling stimulates proliferation and inhibits differentiation of testicular Sertoli cells. A decline in activin levels at puberty corresponds with the differentiation of Sertoli cells that is required to sustain spermatogenesis. In this study, we consider whether terminally differentiated Sertoli cells can revert to a functionally immature phenotype in response to activin A. To increase systemic activin levels, the right tibialis anterior muscle of 7-wk-old C57BL/6J mice was transduced with an adeno-associated virus (rAAV6) expressing activin A. We show that chronic activin signaling reduces testis mass by 23.5% compared with control animals and induces a hypospermatogenic phenotype, consistent with a failure of Sertoli cells to support spermatogenesis. We use permeability tracers and transepithelial electrical resistance measurements to demonstrate that activin potently disrupts blood-testis-barrier function in adult mice and ablates tight junction formation in differentiated primary Sertoli cells, respectively. Furthermore, increased activin signaling reinitiates a program of cellular proliferation in primary Sertoli cells as determined by 5-ethynyl-2'-deoxyuridine incorporation. Proliferative cells reexpress juvenile markers, including cytokeratin-18, and suppress mature markers, including claudin-11. Thus, activin A is the first identified factor capable of reprogramming Sertoli cells to an immature, dedifferentiated phenotype. This study indicates that activin signaling must be strictly controlled in the adult in order to maintain Sertoli cell function in spermatogenesis.