title: Homer1 alternative splicing is regulated by gonadotropin-releasing hormone and modulates gonadotropin gene expression.
abstract: Hypothalamic gonadotropin-releasing hormone (GnRH) plays a critical role in reproductive physiology by regulating follicle-stimulating hormone (FSH) and luteinizing hormone (LH) gene expression in the pituitary. Analysis of gonadotrope deep-sequencing data identified a global regulation of pre-mRNA splicing by GnRH. Homer1, a gene encoding a postsynaptic density scaffolding protein, was selected for further study. Homer1 expresses a short splice form, Homer1a, and more-abundant long transcripts Homer1b/c. GnRH induced a modest increase in Homer1b/c expression and a dramatic increase in the Homer1a splice form. G protein knockdown studies suggested that the Homer1 induction, but not the regulated splicing, was Gαq/11 dependent. Phosphorylation of the splicing regulator SRp20 was found to be induced by GnRH. SRp20 depletion attenuated the GnRH-induced increase in the Homer1a-to-Homer1b/c ratio and modulated the effects of GnRH on FSHβ and LHβ expression. Homer1 gene knockdown resulted in increased GnRH-induced FSHβ and LHβ transcript levels. Furthermore, splice-form-specific reduction of Homer1b/c increased both FSHβ and LHβ mRNA induction, whereas reduction of Homer1a had the opposite effect on FSHβ induction. These results indicate that the regulation of Homer1 splicing by GnRH contributes to gonadotropin gene control.
authors.affiliation: Center for Translational Systems Biology, Department of Neurology, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NewYork, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Maria D
authors.initials: MD
authors.lastname: Chikina
authors.forename: Hanna
authors.initials: H
authors.lastname: Pincas
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Sealfon
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005640:Follicle Stimulating Hormone / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D007987:Gonadotropin-Releasing Hormone / Q000502:physiology*; D000072233:Homer Scaffolding Proteins; D037101:Luteinizing Hormone, beta Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D016601:RNA-Binding Proteins / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D015533:Transcriptional Activation
chemical_list: D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; C000606623:Homer1 protein, mouse; D037101:Luteinizing Hormone, beta Subunit; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; C106161:Srsf3 protein, mouse; D000068103:Serine-Arginine Splicing Factors; D007987:Gonadotropin-Releasing Hormone; D005640:Follicle Stimulating Hormone