Wt1 dictates the fate of fetal and adult Leydig cells during development in the mouse testis

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Article (peer-reviewed)

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Wilms' tumor 1 (Wt1) is a tumor suppressor gene encoding ~24 zinc-finger transcription factors. In the mammalian testis, Wt1 is mostly expressed by Sertoli cells (SCs), involving in testis development, spermatogenesis and adult Leydig cell (ALC) steroidogenesis. Global knockout (KO) of Wt1 is lethal in mice due to defects in embryogenesis. Herein, we showed that Wt1 is involved in regulating fetal Leydig cell (FLC) degeneration and ALC differentiation during testicular development. Using Wt1^-/flox; Amh-Cre mice that specifically deleted Wt1 in the SCs versus age-matched wild-type (WT) controls, FLC-like-clusters were found in Wt1-deficient testes which remained mitotically active from postnatal day 1 (P1) to P56, and no ALC was detected at these ages. Leydig cells in mutant adult testes displayed morphological features of FLC. Also, FLC-like cells in adult mutant testes had reduced expression in ALC-associated genes Ptgds, Sult1e1, Vcam1, Hsd11b1, Hsd3b6 and Hsd17b3, but high expression of FLC-associated genes Thbs2 and Hsd3b1. While serum LH and testosterone level in mutant mice was not different from controls, intratesticular testosterone level was significantly reduced. Deletion of Wt1 gene also perturbed the expression of steroidogenic enzymes Star, P450c17, Hsd3b6, Hsd3b1, Hsd17b1 and Hsd17b3. FLCs in adult mutant testes failed to convert androstenedione to testosterone due to a lack of Hsd17b3, and this defect was rescued by co-culturing with fetal SCs. In summary, FLC-like cells in mutant testes are putative FLCs which remain mitotically active in adult mice, illustrating Wt1 dictates the fate of FLC and ALC during postnatal testis development.