ECE2019 Guided Posters Reproductive Axis (9 abstracts)
Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3
Juan M Castellano 1 , Violeta Heras 1 , Susana Sangiao-Alvarellos 2 , Maria Manfredi-Lozano 1 , María J Sánchez-Tapia 1 , Francisco Ruiz-Pino 1 , Juan Roa 1 , Maribel Lara-Chica 1 , Rosario Morrugares-Carmona 1 , Ana P Abreu 3 , Denise Belsham 4 , María J Vázquez 1 , Marco A Calzado 1 , Leonor Pinilla 1 , Francisco Gaytán 1 , Ana C Latronico 5 , Ursula B Kaiser 3 & Manuel Tena-Sempere 1
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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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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