The ERK-dependent signalling is stage-specifically modulated by FSH, during primary Sertoli cell maturation

Primary cultures of Sertoli cells provide an interesting model to study how signalling pathways induced by a single hormone in a single cell type evol ve, depending. on the developmental stage. In vivo, follicle-stimulating ho rmone (FSH) induces proliferation of Sertoli cells in neonate and controls the subsequent differentiation of the entire population. Molecular mechanis ms underlying Sertoli cell pleiotropic responses to FSH have long been inve stigated. But to date, only cAMP-dependent kinase (PKA) activation has been reported to account for most FSH biological activities in male. Here, we d emonstrate that FSH activates the ERK MAP kinase pathway following dual cou pling of the FSH-R both to Gs and to Gi heterotrimeric proteins, in a PKA- and also Src-dependent manner. This activation is required for FSH-induced proliferation of Sertoli cells isolated 5 days after birth. Consistently, w e show that the ERK-mediated FSH mitogenic effect triggers upregulation of cyclin D1. In sharp contrast, at 19 days after birth, as cells proceed thro ugh their differentiation program, the ERK pathway is dramatically inhibite d by FSH treatment. Taken together, these results show that FSH can exert o pposite effects on the ERK signalling cascade during the maturation process of Sertoli cells. Thus, signalling modules triggered by the FSH-R evolve d ynamically throughout development of FSH natural target cells.