Role of p21 activated kinases in the neuroendocrine actions of estrogen

In rodents as in most mammals, estrogens and their receptors (ERs) play essential roles in the organization of sexually differentiated neural systems during development. Perinatal androgen secretions in males are aromatized to estrogens, which in turn can direct the organization of neural systems that subsequently control sexual behavior and reproductive hormone secretions in adulthood. In adult females, estrogens-principally estadiol-17beta (E 2)-exert several important activational effects on reproductive neuroendocrine systems via ERs in target forebrain neurons. Ovarian E2 secretions exert feedback actions in preoptic-hypothalamic neurons that maintain homeostatic control over gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH) secretions. This thesis examined cellular and molecular processes that mediate E2's actions in the developing and adult brain. The studies specifically tested the hypothesis that p21-activated kinase 1 (PAK1) functions as a downstream node for E2-signaling pathways, and may thereby mediate E2 negative and positive feedback effects in adult females. ERalpha is known to activate both classical and non-classical signaling pathways in target cells. To distinguish these ERalpha-signaling pathways in the regulation of these processes, I utilized a mouse model in which the mutant ERalpha (E207A/G208A; AA) can only signal through non-classical pathways (ERalpha-/AA).;In adult female mice, E2 induces both PAK1 expression and rapid PAK1 phosphorylation (pPAK1) in brain areas critical to GnRH/LH secretion. These effects are mediated by non-classical ERalpha-signaling mechanisms. Inhibition of PAK results in a blockage of rapid E2 suppression of LH secretion, and attenuated LH surges. The findings implicate PAK1 as an important component of ERalpha-signaling in the expression of negative and positive feedback actions of E2. Furthermore, they demonstrated that these actions are exerted, at least in part, through non-classical ERalpha-signaling mechanisms in the brain. The studies in neonates revealed that pPAK expression is sexually differentiated in specific regions in the developing brain. The enhanced expression of pPAK in the male occurs through multiple ERalpha-dependent and/or -independent signaling mechanisms in a region specific manner.;Together, these data expands our current understanding of molecular and cellular mechanisms by which E2 exerts its organizational effects on brain sexual differentiation and activational effects on homeostatic neuroendocrine feedback.