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Exploring possible new receptors and signaling pathways that may contribute to the modulatory effect of relaxin on proliferation and differentiation of Sertoli cells

Abstract

An especially important time of the physiology of Sertoli cells is its transition from a proliferative to a differentiation stage. This process needs to be finely adjusted because it will determine the appropriate support of the germ cell line in adult life and the fertility of the individual. Immature Sertoli cells proliferate and several factors affect this process, including FSH, estradiol and testosterone, and a number of paracrine factors. Sertoli cells from 15-day-old rats proliferate, but they are close to differentiate. At this stage, FSH promotes intense increase in cAMP production, in addition to inhibiting the phosphorylation of ERK1/2 and AKT, and changes gene expression in a complex way, suggesting that, in this transition phase, FSH although still stimulates cell proliferation, starts to direct cells to differentiation. Conversely, the paracrine factor relaxin stimulates MEK/ERK1/2 and PI3K/AKT pathways to promote proliferation of Sertoli cell of 15-day-old rats. At the same time, relaxin inhibits cAMP production in these cells. This fact is puzzling because the best known signaling mechanism of relaxin is precisely the activation of cAMP production, stimulated after interaction of the peptide with the G protein-coupled receptor RXFP1. It remains to be characterized the mechanism of this differential inhibiting action of relaxin on cAMP production in testis. This inhibition appears to involve coupling to Gi, but the involvement of one of the alternative splice variants of RXFP1, which may act as an antagonist of the action of the peptide remains to be clarified. In addition, relaxin may also activate the NO/cGMP/PKG pathway through activation of the glucocorticoid receptor (GR). The objective of this study is to explore more extensively the mechanism of relaxin action in testis, investigating the possible role of alternative splice variants of RXFP1, the involvement of GR, and the involvement of the NO/cGMP/PKG pathway. Furthermore, we want to explore further the repercussion of the opposite effects of relaxin and FSH on signaling pathways and evalute the effect of these hormones on the expression of marker genes of immature (aromatase) or differentiating cells (inhibin alpha and androgen receptor), before and after silencing endogenous relaxin. This study will contribute to clarify the events that influence the establishment of the differentiation stage of Sertoli cells, which is essential for the maintenance of spermatogenesis in adulthood. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
NASCIMENTO, ALINE R.; MACHERONI, CARLA; LUCAS, THAIS F. G.; PORTO, CATARINA S.; LAZARI, MARIA F. M. Crosstalk between FSH and relaxin at the end of the proliferative stage of rat Sertoli cells. Reproduction, v. 152, n. 6, p. 613-628, DEC 2016. Web of Science Citations: 5.

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