ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 63 GP62 | DOI: 10.1530/endoabs.63.GP62

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

Juan M Castellano1, Violeta Heras1, Susana Sangiao-Alvarellos2, Maria Manfredi-Lozano1, María J Sánchez-Tapia1, Francisco Ruiz-Pino1, Juan Roa1, Maribel Lara-Chica1, Rosario Morrugares-Carmona1, Ana P Abreu3, Denise Belsham4, María J Vázquez1, Marco A Calzado1, Leonor Pinilla1, Francisco Gaytán1, Ana C Latronico5, Ursula B Kaiser3 & Manuel Tena-Sempere1

1Department of Cell Biology, Physiology and Immunology, University of Córdoba & Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Córdoba, Spain; 2Department of Medicine, Faculty of Health Sciences, University of A Coruña, Instituto de Investigación Biomédica (INIBIC), University Hospital A Coruña, A Coruña, Spain; 3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women‘s Hospital and Harvard Medical School, Boston, USA; 4Department of Physiology, Medical Sciences Building, University of Toronto, Toronto, Canada; 5Unidade 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, Sao Paulo, Brazil.

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’-untranslated region (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.

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