E2F1 regulates testicular descent and controls spermatogenesis by influencing WNT4 signaling

Development. 2021 Jan 13;148(1):dev191189. doi: 10.1242/dev.191189.

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.

Keywords: Copy number variations; Cryptorchidism; E2f1; Infertility; Testicular cancer; Wnt4.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / pathology
  • Animals
  • Animals, Newborn
  • Blood-Testis Barrier / pathology
  • Cell Cycle / genetics
  • Cryptorchidism / genetics
  • Cryptorchidism / pathology
  • E2F1 Transcription Factor / deficiency
  • E2F1 Transcription Factor / metabolism*
  • Fertility
  • Gene Expression Regulation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Signal Transduction
  • Spermatogenesis*
  • Spermatozoa / metabolism
  • Testis / metabolism*
  • Testis / pathology
  • Wnt4 Protein / metabolism*

Substances

  • E2F1 Transcription Factor
  • Wnt4 Protein