Androgen Receptor in Sertoli Cells Is Not Required for Testosterone‐Induced Suppression of Spermatogenesis, but Contributes to Sertoli Cell Organization in Utp14b^jsd Mice

Abstract

Testosterone acting through the androgen receptor (AR) maintains the arrest of spermatogonial differentiation in juvenile spermatogonial depletion (jsd mutation in the Utp14b gene) mutant adult male mice. It is not known which of the somatic cell types expressing AR mediates this inhibition. To determine if Sertoli cells are responsible, we selectively eliminated AR in Sertoli cells in jsd mice containing a floxed-Ar gene and an anti-Müllerian hormone-Cre transgene. In these Sertoli ARknockout (SCARKO)-jsd mice, spermatogonial differentiation did not recover. However, the normal organization of Sertoli cell nuclei was drastically disrupted in SCARKO-jsd mice, compared to SCARKO or jsd mice. In addition, the extent of ectoplasmic specializations was reduced, tight junctions were not found, vinculin, an anchoring protein found in ectoplasmic specializations, became uniformly distributed in the cytoplasm, and the adult Sertoli cells showed excess heterochromatin subjacent to their nuclear envelope. Despite the abnormalities in Sertoli cells in SCARKO-jsd mice, global suppression of testosterone action and levels was still effective in restoring the differentiated germ cells, and this was accompanied by an improved arrangement of Sertoli cell nuclei. We conclude that Sertoli cells are not targets for the testosterone-mediated inhibition of spermatogonial differentiation in jsd mice, and both AR in Sertoli cells and the presence of differentiated germ cells contribute to maintaining the organization of Sertoli cells within the seminiferous tubules.

BMP6 Regulates Proliferation and Apoptosis of Human Sertoli Cells Via Smad2/3 and Cyclin D1 Pathway and DACH1 and TFAP2A Activation

“…Androgen receptor (AR), another factor expressed in Sertoli cells, is crucial for the development and the maintenance of male germ cells in testis37. Sertoli cells specific AR-knockout mice have smaller testes with hypotestosteronemia, arrested spermatogenesis, no mature sperm in epididymides, and defective seminiferous tubule development383940414243. In this study, a significant reduction of AR was seen in human Sertoli cells when BMP6 was knocked down.…”

Androgen Receptor (AR) Physiological Roles in Male and Female Reproductive Systems: Lessons Learned from AR-Knockout Mice Lacking AR in Selective Cells1

“…Results of a subsequent study suggested that both Sertoli cell AR and the presence of differentiated germ cells are required for maintenance of the Sertoli cell organization within the seminiferous tubules [46]. One of the cytoskeletal components, beta-tubulin isotype Tubb3, an AR-target gene, was found to be differentially regulated between P10 and adulthood in SC-ARKO testes compared to Wt testes [47].…”

“…AR ÀEX3 CMV-Cre All cell types Female-like appearance, small testes with cryptorchidism, and complete androgen insensitivity [31]. SC-ARKO AMH-Cre Sertoli cells Smaller testes with hypotestosteronemia, infertility with spermatogenesis arrested and no mature sperm in epididymides [29,30,33,34], moderately decreased Leydig cell number [35], and defective seminiferous tubule development [44,46]. SC-AR ÀEx3 AMH-Cre or Abp-Cre…”

Testosterone signaling and the regulation of spermatogenesis

“…21 The use of Cre-Lox conditional knockout techniques to create mice in which the loss of AR is restricted to Sertoli cells (SCARKO mice) has allowed for a more precise determination of review review spermatogonial germ cells 28 and that Sertoli cell nuclei show signs of immaturity and are abnormally localized away from the basal lamina. 22,26,28,29 The implications of these last two characteristics of AR deficient Sertoli cells for maintaining spermatogenesis have not yet been investigated.…”