Crosstalk between FSH and relaxin at the end of the proliferative stage of rat Sertoli cells.
Follicle-stimulating hormone (FSH) stimulates the proliferation of immature Sertoli cells through the activation of PI3K/AKT/mTORC1 and MEK/ERK1/2 pathways. Mature Sertoli cells stop proliferating and respond to FSH by stimulating cAMP production. To gain insight into possible mechanisms involved in this switch as well as the impact of paracrine factors that stimulate cell proliferation, we analyzed the effects of FSH and relaxin on intracellular signaling pathways involved with proliferation and differentiation in Sertoli cells from 15-day-old rats, which are close to the transition between the two stages. FSH stimulated3H-thymidine incorporation and cyclin D1 expression, changes associated with proliferation. In contrast, FSH inhibited AKT and ERK1/2 phosphorylation, activated cAMP production and induced changes in several cell cycle genes that were compatible with differentiation. Relaxin also stimulated3H-thymidine incorporation but increased phosphorylation of ERK1/2 and AKT. When both hormones were added simultaneously, relaxin attenuated FSH-mediated inhibition of ERK1/2 and AKT phosphorylation and FSH-mediated activation of cAMP production. FSH but not relaxin increased CREB phosphorylation, and relaxin but not FSH shifted NF-κB expression from the cytoplasm to the nucleus. Relaxin did not inhibit the effects of FSH on inhibin α and Bcl2 expression. We propose that at this time of Sertoli cell development, FSH starts to direct cells to differentiation through activation of cAMP/CREB and inhibition of ERK1/2 and AKT pathways. Relaxin counteracts FSH signaling through the inhibition of cAMP and activation of ERK1/2, AKT and NF-κB, but does not block the differentiation process triggered by FSH.
Section of Experimental EndocrinologyDepartment of Pharmacology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, SP, Brazil.
Aline R
AR
Nascimento
Section of Experimental EndocrinologyDepartment of Pharmacology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, SP, Brazil.
Carla
C
Macheroni
Section of Experimental EndocrinologyDepartment of Pharmacology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, SP, Brazil.
Thais F G
TF
Lucas
Section of Experimental EndocrinologyDepartment of Pharmacology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, SP, Brazil.
Catarina S
CS
Porto
Section of Experimental EndocrinologyDepartment of Pharmacology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, SP, Brazil lazari@unifesp.br.
Maria F M
MF
Lazari
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006728:Hormones / Q000494:pharmacology; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012065:Relaxin / Q000494:pharmacology*; D012708:Sertoli Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D018797:Cell Cycle Proteins; D006728:Hormones; D005640:Follicle Stimulating Hormone; D012065:Relaxin