Molecular Mechanisms and Signaling Pathways Involved in Sertoli Cell Proliferation

Abstract

Sertoli cells are somatic cells present in seminiferous tubules which have essential roles in regulating spermatogenesis. Considering that each Sertoli cell is able to support a limited number of germ cells, the final number of Sertoli cells reached during the proliferative period determines sperm production capacity. Only immature Sertoli cells, which have not established the blood-testis barrier, proliferate. A number of hormonal cues regulate Sertoli cell proliferation. Among them, FSH, the insulin family of growth factors, activin, and cytokines action must be highlighted. It has been demonstrated that cAMP/PKA, ERK1/2, PI3K/Akt, and mTORC1/p70SK6 pathways are the main signal transduction pathways involved in Sertoli cell proliferation. Additionally, c-Myc and hypoxia inducible factor are transcription factors which participate in the induction by FSH of various genes of relevance in cell cycle progression. Cessation of proliferation is a pre-requisite to Sertoli cell maturation accompanied by the establishment of the blood-testis barrier. With respect to this barrier, the participation of androgens, estrogens, thyroid hormones, retinoic acid and opioids has been reported. Additionally, two central enzymes that are involved in sensing cell energy status have been associated with the suppression of Sertoli cell proliferation, namely AMPK and Sirtuin 1 (SIRT1). Among the molecular mechanisms involved in the cessation of proliferation and in the maturation of Sertoli cells, it is worth mentioning the up-regulation of the cell cycle inhibitors p21Cip1, p27Kip, and p19INK4, and of the gap junction protein connexin 43. A decrease in Sertoli cell proliferation due to administration of certain therapeutic drugs and exposure to xenobiotic agents before puberty has been experimentally demonstrated. This review focuses on the hormones, locally produced factors, signal transduction pathways, and molecular mechanisms controlling Sertoli cell proliferation and maturation. The comprehension of how the final number of Sertoli cells in adulthood is established constitutes a pre-requisite to understand the underlying causes responsible for the progressive decrease in sperm production that has been observed during the last 50 years in humans.

Keywords: Sertoli cells; maturation; proliferation; signal transduction; xenobiotics.

Figure 1

Schematic representation of the main regulators of proliferation and of cessation of proliferation and/or maturation of Sertoli cells. Hormones and paracrine factors that stimulate proliferation are depicted in green and those that promote the cessation of proliferation and/or maturation are depicted in blue. Signal transduction pathways and possible mechanisms involved are also included in the schema. FSH, Follicle-Stimulating Hormone; E2, 17β-estradiol; ERα, Estrogen Receptor α; GPER, G protein-coupled estrogen receptor; IGF-1, Insulin-like growth factor 1; ins, insulin; PI3K, phosphatidyl-inositide-3 kinase; ERK1/2, extracellular regulated kinase 1/2; PKA, cAMP-dependent kinase; mTORC1, mammalian target of rapamycin complex 1; HIF2, Hypoxia inducible factor 2; TH, thyroid hormones; RA, retinoic acid; ERβ, Estrogen Receptor β; AMPK, AMP-activated protein kinase; SIRT1, sirtuin 1; Cx43, connexin 43.