E2F1 regulates testicular descent and controls spermatogenesis by influencing WNT4 signaling

Abstract

Cryptorchidism is the most common urologic birth defect in men and is a predisposing factor of male infertility and testicular cancer, yet the etiology remains largely unknown. E2F1 microdeletions and microduplications contribute to cryptorchidism, infertility and testicular tumors. Although E2f1 deletion or overexpression in mice causes spermatogenic failure, the mechanism by which E2f1 influences testicular function is unknown. This investigation revealed that E2f1-null mice develop cryptorchidism with severe gubernacular defects and progressive loss of germ cells resulting in infertility and, in rare cases, testicular tumors. It was hypothesized that germ cell depletion resulted from an increase in WNT4 levels. To test this hypothesis, the phenotype of a double-null mouse model lacking both Wnt4 and E2f1 in germ cells was analyzed. Double-null mice are fertile. This finding indicates that germ cell maintenance is dependent on E2f1 repression of Wnt4, supporting a role for Wnt4 in germ cell survival. In the future, modulation of WNT4 expression in men with cryptorchidism and spermatogenic failure due to E2F1 copy number variations may provide a novel approach to improve their spermatogenesis and perhaps their fertility potential after orchidopexy.

Protein kinase A drives paracrine crisis and WNT4-dependent testis tumor in Carney complex

“…This observation is reminiscent of a previously described mouse model showing that SC-specific β-catenin constitutive activation leads to WNT4 overproduction and a subsequent decrease in the spermatogonial stem cell activity responsible for apoptosis and loss of GCs (42). In a report analyzing the testis of E2f1-Wnt4 double-KO mice, Jorgez et al specified that germ-line maintenance was dependent on Wnt4 repression by E2f1, supporting a role of Wnt4 in GC survival (68). Interestingly, in response to Prkar1a inactivation, our models also show WNT/β-catenin activation attested by upregulation of Wnt4 and Ctnnb1 expression and by increased accumulation of the β-catenin active form (i.e., dephosphorylated).…”

PRSS50 is a testis protease responsible for proper sperm tail formation and function

“…Testis and epididymis were dissected from animals, placed immediately in cold drops of modified Karnovsky's fixative (Karnovsky, 1965), and processed and imaged as previously published (Jorgez et al, 2021).…”

Retinoblastoma-E2F Transcription Factor Interplay Is Essential for Testicular Development and Male Fertility

“…This is apparent also in the testis. E2F1 has been associated with progressive degeneration of the seminiferous epithelium ( 43 , 82 – 84 ), GSC maintenance ( 43 , 84 ), apoptosis of germ cells ( 43 , 85 ) and Sertoli cells ( 44 ), germ cell neoplasia in situ ( 86 ), testicular tumors ( 82 ), testicular descent in human ( 87 , 88 ) and mouse ( 84 ), and human male infertility ( 87 , 88 ).…”