Abstract
The Sertoli cells are critical regulators of testis differentiation and development. In the adult, however, their known function is restricted largely to maintenance of spermatogenesis. To determine whether the Sertoli cells regulate other aspects of adult testis biology we have used a novel transgenic mouse model in which Amh-Cre induces expression of the receptor for Diphtheria toxin (iDTR) specifically within Sertoli cells. This causes controlled, cell-specific and acute ablation of the Sertoli cell population in the adult animal following Diphtheria toxin injection. Results show that Sertoli cell ablation leads to rapid loss of all germ cell populations. In addition, adult Leydig cell numbers decline by 75% with the remaining cells concentrated around the rete and in the sub-capsular region. In the absence of Sertoli cells, peritubular myoid cell activity is reduced but the cells retain an ability to exclude immune cells from the seminiferous tubules. These data demonstrate that, in addition to support of spermatogenesis, Sertoli cells are required in the adult testis both for retention of the normal adult Leydig cell population and for support of normal peritubular myoid cell function. This has implications for our understanding of male reproductive disorders and wider androgen-related conditions affecting male health.
Highlights
The Sertoli cells are essential regulators of testis differentiation and fetal masculinization through expression of SRY, secretion of AMH and induction of fetal Leydig cell development
We show for the first time that, in addition to their established role in supporting spermatogenesis, the Sertoli cells are critical for maintaining Leydig cell numbers in the adult testis
Sertoli cell specific ablation in Amh-Cre;iDTR mice To determine the fundamental role of Sertoli cells in the adult testis we bred an Amh-Cre+/2 line [41] to mice carrying a Creinducible simian HBEGF [42] (Figure 1A), and confirmed that iDTR expression was restricted to Sertoli cells (Figure 1B)
Summary
The Sertoli cells are essential regulators of testis differentiation and fetal masculinization through expression of SRY, secretion of AMH and induction of fetal Leydig cell development (reviewed in [1,2,3,4]). Even withdrawal of LH support, while reducing testosterone production markedly, has little effect on Leydig cell number [26,27] It is not clear, whether the Sertoli cells continue to play a role in regulating adult Leydig cell maintenance or whether the Leydig cells are largely autonomous, dependent only on hormonal regulation. Similar studies to examine the effects of Sertoli cell ablation on adult testis function have not been possible, as cytotoxins that target the Sertoli cells have not been available To address this need, we have developed a novel transgenic mouse model that permits controlled and specific ablation of Sertoli cells at any chosen age via Diptheria-toxin (DTX)–mediated induction of apoptosis [21]. These findings significantly alter our understanding of adult testis function, with potential implications for male reproductive and general health
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