title: Effects of progesterone and medroxyprogesterone on actin remodeling and neuronal spine formation.
abstract: Sex steroids are important regulators of neuronal cell morphology, and this is critical for gender differences in brain function and dysfunction. Neuronal morphology is controlled by multiprotein complexes including moesin (a member of the ezrin/radixin/moesin family), focal adhesion kinase (FAK), or the Wiskott-Aldrich syndrome protein-family verprolin homologous (WAVE1) protein, controlling dynamic remodeling of the cytoskeleton and cell membrane. We investigated the actions of natural progesterone (P) and of the synthetic progestin medroxyprogesterone acetate (MPA) on actin remodeling, focal adhesion complex formation, and actin branching in rat cortical neurons. Treatment with P and, to a lesser extent, MPA, increases the number and density of dendritic spines. P increases the phosphorylation of moesin, FAK, and WAVE1, and their redistribution toward cell membrane sites where spines are formed. Signaling to moesin is achieved by PR via a Gα/Gβ-dependent signaling to the small GTPase Ras homolog gene family, member A and its related kinase, Rho-associated kinase-2. In parallel, WAVE1 recruitment is triggered by a Gαi/Gβ-dependent signaling of PR to c-Src, FAK, and Rac1 GTPase. Rac1 recruits cyclin-dependent kinase-5, which phosphorylates WAVE1. Silencing of moesin, FAK, or WAVE1 abrogates the increase in dendritic spines induced by progesterone. In all applications, MPA is found to act similar to P, albeit with a lower efficacy. In conclusion, our findings indicate that the control of actin polymerization and branching and focal adhesion complex formation via moesin, FAK, and WAVE1 is a key function of progesterone receptor in neurons, which may be relevant for the regulation of dendritic spine turnover and neuronal plasticity.
authors.affiliation: Molecular and Cellular Gynecological Endocrinology Laboratory, Department of Experimental and Clinical Medicine, University of Pisa, Via Roma, 67, 56100, Pisa, Italy.
authors.forename: Angel Matias
authors.initials: AM
authors.lastname: Sanchez
authors.forename: Marina Ines
authors.initials: MI
authors.lastname: Flamini
authors.forename: Andrea Riccardo
authors.initials: AR
authors.lastname: Genazzani
authors.forename: Tommaso
authors.initials: T
authors.lastname: Simoncini
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D008525:Medroxyprogesterone / Q000494:pharmacology*; D008840:Microfilament Proteins / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D011374:Progesterone / Q000494:pharmacology*; D051381:Rats; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D008840:Microfilament Proteins; D011980:Receptors, Progesterone; D051300:Wiskott-Aldrich Syndrome Protein Family; C071058:moesin; D011374:Progesterone; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D051360:Cyclin-Dependent Kinase 5; D054460:rho-Associated Kinases; D019204:GTP-Binding Proteins; D008525:Medroxyprogesterone