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

Departments of Pathology (R.L.N., C.A.-V., M.M.M.), Molecular and Cellular Biology (R.L.N., M.M.M.), and Molecular and Human Genetics (M.M.M.), Baylor College of Medicine, Houston, Texas 77030; The Jackson Laboratory (R.E.B.), Bar Harbor, Maine 04609; and Department of Orthopaedics (H.A.), Kyoto University, Kyoto 606-8507, Japan

Address all correspondence and requests for reprints to: Martin M. Matzuk, M.D., Ph.D., Stuart Wallace Chair and Professor, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Room S217, Houston, Texas 77030. E-mail: mmatzuk{at}bcm.tmc.edu.

Retinoblastoma protein (RB) plays crucial roles in cell cycle control and cellular differentiation. Specifically, RB impairs the G₁ 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-dependant 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.