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.
Highlights
Sertoli cells represent one of the most complex cells in the organism
Regarding the signal transduction pathways elicited by insulin/IGF-1 system in Sertoli cells, there is general agreement that they can activate phosphatidyl-inositide-3 kinase (PI3K)/Akt and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) signaling pathways and, that this is mediated by IRS2
Concerning the signaling pathways involved in estrogen action in Sertoli cells, Lucas et al [210] have shown that the interaction of E2 with ERα promotes cell proliferation through the activation of NFκB in a PI3K- and a ERK1/2-dependent manner and that this is accompanied by cyclin D1 induction
Summary
Sertoli cells represent one of the most complex cells in the organism. because of their three-dimensional structure and due to their function to create a unique environment which allows germ cell development. From the initial studies of Sertoli [6] significant advances have been made in understanding the functionality of this cell type It is well-known that the gonadotropin Follicle-Stimulating Hormone (FSH) and androgens regulate the proliferation and functional maturation of this cell type. In addition to these classical hormones, a great number of locally produced factors participate in the regulation of Sertoli cells reflecting one of the most representative examples of cell-cell communication [7]. Studies performed by Orth [13, 14] identified fetal and postnatal life in the rat as moments of high mitotic activity From these initial studies that established the basic concepts on Sertoli cell proliferation a great number of investigators have tried to deeply understand the molecular mechanisms underlying this physiological process. Our review will highlight molecular mechanisms related to the above-mentioned processes, i.e., proliferation and maturation, which may be affected by exposure to certain therapeutic drugs or pollutants
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