E4 Transcription Factor 1 (E4F1) Regulates Sertoli Cell Proliferation and Fertility in Mice

Abstract

In the mammalian testes, Sertoli cells are the only somatic cells in the seminiferous tubules that provide structural, nutritional and regulatory support for developing spermatogenic cells. Sertoli cells only proliferate during the fetal and neonatal periods and enter a quiescent state after puberty. Functional evidences suggest that the size of Sertoli cell population determines sperm production and fertility. However, factors that direct Sertoli cell proliferation and maturation are not fully understood. Transcription factor E4F1 is a multifunctional protein that serves essential roles in cell fate decisions and because it interacts with pRB, a master regulator of Sertoli cell function, we hypothesized that E4F1 may have a functional role in Sertoli cells. E4f1 mRNA was present in murine testis and immunohistochemical staining confirmed that E4F1 was enriched in mature Sertoli cells. We generated a conditional knockout mouse model using Amh-cre and E4f1flox/flox lines to study E4F1 fucntion in Sertoli cells and the results showed that E4f1 deletion caused a significant reduction in testis size and fertility. Further analyses revealed that meiosis progression and spermiogenesis were normal, however, Sertoli cell proliferation was impaired and germ cell apoptosis was elevated in the testis of E4f1 conditional knockout mice. On the basis of these findings, we concluded that E4F1 was expressed in murine Sertoli cells and served important functions in regulating Sertoli cell proliferation and fertility.

An overview of novel transcription factors involved in spermatogonial stem cells

“…As a multifunctional transcription factor, E4F1 plays an essential role in cell fate decisions and interacts with Retinoblastoma protein (pRB), a regulator of Sertoli cells [34]. Due to the mortality of the preimplantation embryos in E4F1 knockout mice, the E4F1 is thought as a necessary gene for early embryonic development [32].…”

Cellular and Molecular Insights Into the Etiology of Subfertility/Infertility in Crossbred Bulls (Bos taurus × Bos indicus): A Review

“…A recent study by Rajak et al (2016b) showed that “good” bulls had a significantly higher (25%) proportion of Sertoli cells in testicular cytology compared to “poor” bulls (11%). Sertoli cells are capable of supporting only a finite number of germ cells; the final number of Sertoli cells in a given male sets the upper limit for testicular sperm production ( Waqas et al, 2019 ) and determines the level of male fertility ( Yan et al, 2020 ). A high number of Sertoli cells per spermatogenic cell would be expected to provide sufficient support and nourishment for successful progression of spermatogenesis and for production of good-quality spermatozoa.…”

Transcription factor E4F1 dictates spermatogonial stem cell fate decisions by regulating mitochondrial functions and cell cycle progression

“…E4f1 knockout leads to the exhaustion of the epidermal stem cell pool in skin [ 22 ]; however, its deficiency does not affect the stem cell compartment but instead causes the depletion of multipotent progenitors in the hematopoietic system [ 20 ]. Conditional deletion of E4f1 in Sertoli cells did not cause severe defects in spermatogenesis, indicating its intriguing roles in different tissues [ 26 ]. Because of its essential roles in metabolism, deciphering the function of E4F1 in spermatogenic cells will facilitate the understanding of the metabolic control of SSC fate decisions.…”