Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3.

Autor: Heras V; Department of Cell Biology, Physiology and Immunology, University of Córdoba & Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Cordoba, Spain., Sangiao-Alvarellos S; Department of Medicine, Faculty of Health Sciences, University of A Coruña, A Coruña, Spain, Instituto de Investigación Biomédica (INIBIC), University Hospital A Coruña, A Coruña, Spain., Manfredi-Lozano M; Department of Cell Biology, Physiology and Immunology, University of Córdoba & Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Cordoba, Spain., Sanchez-Tapia MJ; Department of Cell Biology, Physiology and Immunology, University of Córdoba & Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Cordoba, Spain., Ruiz-Pino F; Department of Cell Biology, Physiology and Immunology, University of Córdoba & Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Cordoba, Spain., Roa J; Department of Cell Biology, Physiology and Immunology, University of Córdoba & Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Cordoba, Spain., Lara-Chica M; Department of Cell Biology, Physiology and Immunology, University of Córdoba & Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Cordoba, Spain., Morrugares-Carmona R; Department of Cell Biology, Physiology and Immunology, University of Córdoba & Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Cordoba, Spain., Jouy N; Jean-Pierre Aubert Research Center, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Inserm, UMR-S 1172, Lille, France., Abreu AP; Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America., Prevot V; Jean-Pierre Aubert Research Center, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Inserm, UMR-S 1172, Lille, France., Belsham D; Department of Physiology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada., Vazquez MJ; Department of Cell Biology, Physiology and Immunology, University of Córdoba & Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Cordoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Córdoba, Spain., Calzado MA; Department of Cell Biology, Physiology and Immunology, University of Córdoba & Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Cordoba, Spain., Pinilla L; Department of Cell Biology, Physiology and Immunology, University of Córdoba & Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Cordoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Córdoba, Spain., Gaytan F; Department of Cell Biology, Physiology and Immunology, University of Córdoba & Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Cordoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Córdoba, Spain., Latronico AC; Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, LIM 42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil., Kaiser UB; Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America., Castellano JM; Department of Cell Biology, Physiology and Immunology, University of Córdoba & Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Cordoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Córdoba, Spain., Tena-Sempere M; Department of Cell Biology, Physiology and Immunology, University of Córdoba & Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Cordoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Córdoba, Spain.; FiDiPro Program, Institute of Biomedicine, University of Turku, Kiinamyllynkatu, Turku, Finland.
Jazyk: angličtina
Zdroj: PLoS biology [PLoS Biol] 2019 Nov 07; Vol. 17 (11), pp. e3000532. Date of Electronic Publication: 2019 Nov 07 (Print Publication: 2019).
DOI: 10.1371/journal.pbio.3000532
Abstrakt: Mkrn3, the maternally imprinted gene encoding the makorin RING-finger protein-3, has recently emerged as putative pubertal repressor, as evidenced by central precocity caused by MKRN3 mutations in humans; yet, the molecular underpinnings of this key regulatory action remain largely unexplored. We report herein that the microRNA, miR-30, with three binding sites in a highly conserved region of its 3' UTR, operates as repressor of Mkrn3 to control pubertal onset. Hypothalamic miR-30b expression increased, while Mkrn3 mRNA and protein content decreased, during rat postnatal maturation. Neonatal estrogen exposure, causing pubertal alterations, enhanced hypothalamic Mkrn3 and suppressed miR-30b expression in female rats. Functional in vitro analyses demonstrated a strong repressive action of miR-30b on Mkrn3 3' UTR. Moreover, central infusion during the juvenile period of target site blockers, tailored to prevent miR-30 binding to Mkrn3 3' UTR, reversed the prepubertal down-regulation of hypothalamic Mkrn3 protein and delayed female puberty. Collectively, our data unveil a novel hypothalamic miRNA pathway, involving miR-30, with a prominent role in the control of puberty via Mkrn3 repression. These findings expand our current understanding of the molecular basis of puberty and its disease states.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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