Reprogramming of Sertoli cells to fetal-like Leydig cells by Wt1 ablation

Abstract

Sertoli and Leydig cells, the two major somatic cell types in the testis, have different morphologies and functions. Both are essential for gonad development and spermatogenesis. However, whether these cells are derived from the same progenitor cells and the mechanism regulating the differentiation between these two cell types during gonad development remains unclear. A previous study showed that overactivation of Ctnnb1 (cadherin-associated protein, beta 1) in Sertoli cells resulted in Sertoli cell tumors. Surprisingly, in the present study, we found that simultaneous deletion of Wilms’ Tumor Gene 1 (Wt1) and overactivation of Ctnnb1 in Sertoli cells led to Leydig cell-like tumor development. Lineage tracing experiments revealed that the Leydig-like tumor cells were derived from Sertoli cells. Further studies confirmed that Wt1 is required for the maintenance of the Sertoli cell lineage and that deletion of Wt1 resulted in the reprogramming of Sertoli cells to Leydig cells. Consistent with this interpretation, overexpression of Wt1 in Leydig cells led to the up-regulation of Sertoli cell-specific gene expression and the down-regulation of steroidogenic gene expression. These results demonstrate that the distinction between Sertoli cells and Leydig cells is regulated by Wt1, implying that these two cell types most likely originate from the same progenitor cells. This study thus provides a novel concept for somatic cell fate determination in testis development that may also represent an etiology of male infertility in human patients.

Mapping lineage progression of somatic progenitor cells in the mouse fetal testis

“…Because endogenous WT1 expression in the somatic compartment of the testis becomes restricted to Sertoli cells within the testis cords after E12.5, WT1 could be involved in the maintenance of Sertoli cell identity. In line with this hypothesis, ablation of Wt1 gene in Sertoli cells results in the transformation of Sertoli cells into fetal Leydig-like cells, whereas overexpression of Wt1 in fetal Leydig cells promotes the expression of Sertoli cell-specific genes and suppresses steroidogenic genes (Wen et al, 2014;Zhang et al, 2015). WT1 appears to mediate the cell fate determination of the common progenitor cells to become either Sertoli cells or fetal Leydig cells.…”

Wt1 directs the lineage specification of sertoli and granulosa cells by repressing Sf1 expression

“…Our recent study demonstrated that inactivation of Wt1 in Sertoli cells after sex determination using AMH-Cre mice resulted in the transformation of Sertoli cells to Leydig cells, suggesting that Sertoli and Leydig cells are probably derived from same progenitor cells (Zhang et al, 2015). In control ovary, 3β-HSD-positive thecainterstitial cells are not observed during the embryonic stage.…”

“…Our previous study showed that inactivation of Wt1 in Sertoli cells after sex determination using AMH-Cre mice caused testicular cord disruption (Gao et al, 2006) and Sertoli cells can be reprogrammed into Leydig cells (Gao et al, 2006;Zhang et al, 2015). These studies indicate that Wt1 plays important roles in testis development and Sertoli cell lineage maintenance.…”

Establishment and applications of male germ cell and Sertoli cell lines

“…Sertoli cells can also be reprogrammed to generate functional neurons (Sheng et al 2012) and other cell lineages (e.g. Leydig cells and iPS cells) (Zhang et al 2015) and thus they can have potential clinical value in translation medicine. Furthermore, these cell lines could be exploited to uncover the underlying etiology of male infertility (e.g.…”

“…Sertoli cells can be reprogrammed to pluripotent stem cells (Sun et al 2014), and significantly they are directly converted to morphologic, phenotypic and functional neural stem cells (Sheng et al 2012) and Leydig cells (Zhang et al 2015). Moreover, Sertoli cells are engineered to produce certain proteins that restore cell metabolic function (Kaur et al 2014).…”