Retinoblastoma Protein Plays Multiple Essential Roles in the Terminal Differentiation of Sertoli Cells

Abstract

Retinoblastoma protein (RB) plays crucial roles in cell cycle control and cellular differentiation. Specifically, RB impairs the G(1) to S phase transition by acting as a repressor of the E2F family of transcriptional activators while also contributing towards terminal differentiation by modulating the activity of tissue-specific transcription factors. To examine the role of RB in Sertoli cells, the androgen-dependent somatic support cell of the testis, we created a Sertoli cell-specific conditional knockout of Rb. Initially, loss of RB has no gross effect on Sertoli cell function because the mice are fertile with normal testis weights at 6 wk of age. However, by 10-14 wk of age, mutant mice demonstrate severe Sertoli cell dysfunction and infertility. We show that mutant mature Sertoli cells continue cycling with defective regulation of multiple E2F1- and androgen-regulated genes and concurrent activation of apoptotic and p53-regulated genes. The most striking defects in mature Sertoli cell function are increased permeability of the blood-testis barrier, impaired tissue remodeling, and defective germ cell-Sertoli cell interactions. Our results demonstrate that RB is essential for proper terminal differentiation of Sertoli cells.

MicroRNA-449 and MicroRNA-34b/c Function Redundantly in Murine Testes by Targeting E2F Transcription Factor-Retinoblastoma Protein (E2F-pRb) Pathway

“…The mitotic phase of spermatogenesis requires the active E2F-pRb pathway as evidenced by the fact that E2F1 depletion causes highly reduced spermatogonial proliferation and marked testicular atrophy (54). However, upon the initiation of meiosis, activities of the E2F-pRb pathway appear to be down-regulated probably because this suppression allows male germ cells to exit from the mitotic cell cycle and to enter the meiotic program as suggested by several earlier studies (52,(55)(56)(57). In addition, this suppression may enhance the germinal phenotype by inhibiting mitotic proliferating activity and promoting meiotic gene expression (53).…”

Retinoblastoma protein controls growth, survival and neuronal migration in human cerebral organoids

“…The VLDLR gene encodes a canonical receptor of reelin, which is widely involved in neuronal migration in mice and humans (Cheng et al, 2011;Teixeira et al, 2012); therefore, additional studies are needed to determine whether expression of VLDLR is a cause or consequence of aberrant migration. Previous microarray analyses carried out with Rb1-deficient mouse osteoblasts (Sosa-García et al, 2010) and Sertoli cells (Nalam et al, 2009) have also revealed that Vldlr expression is induced upon the loss of Rb1 expression in these cell types. These data suggest the possibility of conserved regulatory mechanisms across different tissues by which RB regulates VLDLR expression to control cell migration or cholesterol homeostasis.…”

The Blood-Testis Barrier and Its Implications for Male Contraception

“…Other studies have shown that the RB pathway is crucial in cell cycle control and cell differentiation by serving as a master regulator to coordinate cell cycle exit with differentiation (Lipinski and Jacks, 1999;Nguyen and McCance, 2005;Chinnam and Goodrich, 2011;McDuff and Turner, 2011). It was noted that RB(Ϫ/Ϫ) mice appeared normal by postnatal week 6 (that is, they were fertile with normal testis weights and spermatogenesis indistinguishable from wild-type mice); however, by postnatal weeks 10 to 14, these Rb(Ϫ/Ϫ) mice were infertile with severe Sertoli cell dysfunction, and Sertoli cells displayed defective regulation of multiple androgen-regulated genes and most notably a "leaky" BTB (Nalam et al, 2009). These findings thus illustrate that improper terminal differentiation of Sertoli cells seems not to affect the initial establishment of the BTB to support spermatogenesis in rats, but it fails to "maintain" BTB integrity, which in turn perturbs spermatogenesis.…”