E2F1 controls germ cell apoptosis during the first wave of spermatogenesis

Abstract

SummaryCell cycle control during spermatogenesis is a highly complex process owing to the control of the mitotic expansion of the spermatogonial cell population and following meiosis, induction of DNA breaks during meiosis and the high levels of physiological germ‐cell apoptosis. We set out to study how E2F1, a key controller of cell cycle, apoptosis, and DNA damage responses, functions in the developing and adult testis. We first analyzed the expression pattern of E2f1 during post‐natal testis development using RNA in situ hybridization, which showed a differential expression pattern of E2f1 in the adult and juvenile mouse testes. To study the function of E2f1, we took advantage of the E2F1−/− mouse line, which was back‐crossed to C57Bl/6J genetic background. E2f1 loss led to a severe progressive testicular atrophy beginning at the age of 20 days. Spermatogonial apoptosis during the first wave of spermatogenesis was decreased. However, already in the first wave of spermatogenesis an extensive apoptosis of spermatocytes was observed. In the adult E2F1−/− testes, the atrophy due to loss of spermatocytes was further exacerbated by loss of spermatogonial stem cells. Surprisingly, only subtle changes in global gene expression array profiling were observed in E2F1−/− testis at PND20. To dissect the changes in each testicular cell type, an additional comparative analysis of the array data was performed making use of previously published data on transcriptomes of the individual testicular cell types. Taken together, our data indicate that E2F1 has a differential role during first wave of spermatogenesis and in the adult testis, which emphasizes the complex nature of cell cycle control in the developing testis.

E2F1 copy number variations contribute to spermatogenic impairment and cryptorchidism by increasing susceptibility to heat stress

“…E2F1 is expressed in all actively proliferating tissues; therefore, since testis includes spermatogonia cells undergoing thousands of cell divisions during life, a role has been hypothesized for this transcription factor in testicular development (Rotgers et al, 2015). E2F1 is, in fact, a transcription factor belonging to E2F family and whose main function is to trigger the entry into S phase of cell cycle or apoptotic process.…”

“…E2F1 is, in fact, a transcription factor belonging to E2F family and whose main function is to trigger the entry into S phase of cell cycle or apoptotic process. E2F1 is expressed in all actively proliferating tissues; therefore, since testis includes spermatogonia cells undergoing thousands of cell divisions during life, a role has been hypothesized for this transcription factor in testicular development (Rotgers et al, 2015). In particular, it has been demonstrated that mouse E2f1 protein plays an important role in the first wave of spermatogenesis and in adult mouse testes (Rotgers et al, 2015).…”

Functional role of GKAP1 in the regulation of male germ cell spontaneous apoptosis and sperm number

“…Spermatogenesis is maintained by a dynamic balance between germ cell proliferation and apoptosis. Germ cell proliferation and apoptosis generally regulates sperm numbers (Rotgers, Nurmio, Pietila, Cisneros‐Montalvo, & Toppari, ). We detected PCNA and BrdU in mouse testes, as many researchers used these two proteins to evaluate cell proliferation (Anjum, Krishna, & Tsutsui, ; Figueiredo, Franca, Hess, & Costa, ; Munoz‐Velasco, Ortiz, Echeverria, Escobar, & Vazquez‐Nin, ; Roy, Chenkual, & Gurusubramanian, ).…”

Diverse roles for CDK‐associated activity during spermatogenesis

“…This results in the loss of germ cells and subfertility by 3 months of age. This phenotype was also described to progressively worsen with age suggesting that, E2F signaling, at least via E2F1 is required for normal spermatogenesis . Similarly to the conditional Rb1 knockout, E2f1 −/− testis exhibit a depletion of self‐renewing SSCs .…”

“…This phenotype was also described to progressively worsen with age suggesting that, E2F signaling, at least via E2F1 is required for normal spermatogenesis [141][142][143]. Similarly to the conditional Rb1 knockout, E2f1 À/À testis exhibit a depletion of self-renewing SSCs [143]. Additionally, during the first waves of spermatogenesis, the apoptotic removal of spermatogonia required for the correct establishment of germ/cell/Sertoli cell ratios [144][145][146] was noted to be perturbed and increased apoptosis was observed when these cells entered meiosis.…”