title: Gonadotrope-specific deletion of Dicer results in severely suppressed gonadotropins and fertility defects.
abstract: Pituitary gonadotropins follicle-stimulating hormone and luteinizing hormone are heterodimeric glycoproteins expressed in gonadotropes. They act on gonads and promote their development and functions including steroidogenesis and gametogenesis. Although transcriptional regulation of gonadotropin subunits has been well studied, the post-transcriptional regulation of gonadotropin subunits is not well understood. To test if microRNAs regulate the hormone-specific gonadotropin β subunits in vivo, we deleted Dicer in gonadotropes by a Cre-lox genetic approach. We found that many of the DICER-dependent microRNAs, predicted in silico to bind gonadotropin β subunit mRNAs, were suppressed in purified gonadotropes of mutant mice. Loss of DICER-dependent microRNAs in gonadotropes resulted in profound suppression of gonadotropin-β subunit proteins and, consequently, the heterodimeric hormone secretion. In addition to suppression of basal levels, interestingly, the post-gonadectomy-induced rise in pituitary gonadotropin synthesis and secretion were both abolished in mutants, indicating a defective gonadal negative feedback control. Furthermore, mutants lacking Dicer in gonadotropes displayed severely reduced fertility and were rescued with exogenous hormones confirming that the fertility defects were secondary to suppressed gonadotropins. Our studies reveal that DICER-dependent microRNAs are essential for gonadotropin homeostasis and fertility in mice. Our studies also implicate microRNAs in gonadal feedback control of gonadotropin synthesis and secretion. Thus, DICER-dependent microRNAs confer a new layer of transcriptional and post-transcriptional regulation in gonadotropes to orchestrate the hypothalamus-pituitary-gonadal axis physiology.
authors.affiliation: From the Departments of Molecular and Integrative Physiology.
authors.forename: Huizhen
authors.initials: H
authors.lastname: Wang
authors.affiliation: From the Departments of Molecular and Integrative Physiology.
authors.forename: Ian
authors.initials: I
authors.lastname: Graham
authors.affiliation: Flow Cytometry Core Laboratory, University of Kansas Medical Center, Kansas City, Kansas 66160.
authors.forename: Richard
authors.initials: R
authors.lastname: Hastings
authors.affiliation: From the Departments of Molecular and Integrative Physiology.
authors.forename: Sumedha
authors.initials: S
authors.lastname: Gunewardena
authors.affiliation: Department of Molecular and Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, and.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Brinkmeier
authors.affiliation: Departments of Internal Medicine, Cell Biology, and Biochemistry, Texas Tech University, Lubbock, Texas 79430.
authors.forename: P Michael
authors.initials: PM
authors.lastname: Conn
authors.affiliation: Department of Molecular and Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, and.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Camper
authors.affiliation: From the Departments of Molecular and Integrative Physiology, Center for Reproductive Sciences, Institute for Reproductive Health and Regenerative Medicine, and tkumar@kumc.edu.
authors.forename: T Rajendra
authors.initials: TR
authors.lastname: Kumar
mesh_terms: D000818:Animals; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005298:Fertility / Q000235:genetics / Q000502:physiology; D052681:Gonadotrophs / Q000378:metabolism*; D006062:Gonadotropins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*
chemical_list: D006062:Gonadotropins; D035683:MicroRNAs; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: Glycoprotein; MicroRNA (miRNA); Pituitary Gland; Reproduction; Secretion