Receptors and signaling pathways involved in proliferation and differentiation of Sertoli cells

Abstract

The identification of the hormones and other factors regulating Sertoli cell survival, proliferation, and maturation in neonatal, peripubertal, and pubertal life remains one of the most critical questions in testicular biology. The regulation of Sertoli cell proliferation and differentiation is thought to be controlled by cell-cell junctions and a set of circulating and local hormones and growth factors. In this review, we will focus on receptors and intracellular signaling pathways activated by androgen, follicle-stimulating hormone, thyroid hormone, activin, retinoids, insulin, insulin-like growth factor, relaxin, and estrogen, with special emphasis on estrogen receptors. Estrogen receptors activate intracellular signaling pathways that converge on cell cycle and transcription factors and play a role in the regulation of Sertoli cell proliferation and differentiation.

Keywords: androgen receptor; estrogen receptor; follicle-stimulating hormone receptor; relaxin receptor; thyroid hormone receptor.

Figure 1. The proposed mechanism for the role of estrogen receptors on Sertoli cell proliferation and differentiation. E2 (or the selective ligand) interacts with ESR1 and induces activation of ERK1/2 and PI3K/AKT pathways, and translocation of the transcription factor NFKB to the nucleus, to activate expression of CCND1 (cyclin D1) and cell proliferation. Interaction of ESR2 with E2 (or the selective ligand) induces activation of PI3K/AKT pathway and phosphorylation of the transcription factor CREB, which induces expression of factors involved in inhibition of cell proliferation and/or start of cell differentiation: CDKN1B (p27^kip1), GATA-1, and DMRT1. E2 (or the selective ligand) interacts with GPER and induces transactivation of EGFR via activation of SRC by G-protein βγ subunits that promotes a metalloprotease-dependent release of EGFR ligands, with a consequent activation of ERK1/2 and PIK3 pathways, which in turn triggers an increase in the expression of BCL2 and a decrease in the expression of BAX (for a review, see ref. 97). See text for more details.