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

• DOI: 10.1371/journal.pbio.3000532
• Publication Date: 2019-11-07T18:56:07Z
• Authors: Violeta Heras; Susana Sangiao-Al...; Maria Manfredi-Lo...; María J. Sanchez-...; Francisco Ruiz-Pino; Juan Roa; Maribel Lara-Chica; Rosario Morrugare...; Nathalie Jouy; Ana P. Abreu; Vincent Prevot; Denise Belsham; Maria J. Vazquez; Marco A. Calzado; Leonor Pinilla; Francisco Gaytan; Ana C. Latronico; Ursula B. Kaiser; Juan M. Castellano; Manuel Tena-Sempere
• Keywords: Male; 0301 basic medicine; análisis de secuencias; QH301-705.5; Binding sites; Ubiquitin-Protein Ligases; Hypothalamus; Sexual maturation; regulación de la expresión génica; hipotálamo; ratas; Cell Line; 03 medical and health sciences; Animals; Sexual Maturation; Biology (General); Gene expression regulation, developmental; [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism; MicroARNs; 0303 health sciences; Binding Sites; Regulación del desarrollo de la expresión génica; Línea celular; sitios de unión; ta1182; Gene Expression Regulation, Developmental; maduración sexual; línea celular; Sequence analysis, DNA; Sequence Analysis, DNA; [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism; microARN; ubicuitina-proteína ligasas; Rats; Ubiquitin-protein ligases; MicroRNAs; Sitios de unión; Gene Expression Regulation; INIBIC; animales; Female; Cell line; Sequence Analysis; Hipotálamo; Research Article

Mkrn3, the maternally imprinted gene encoding makorin RING-finger protein-3, has recently emerged as putative pubertal repressor, evidenced by central precocity caused MKRN3 mutations in humans; yet, molecular underpinnings of this key regulatory action remain largely unexplored. We report herein that microRNA, miR-30, with three binding sites a highly conserved region its 3′ UTR, operates repressor Mkrn3 to control onset. Hypothalamic miR-30b expression increased, while mRNA and protein content decreased, during rat postnatal maturation. Neonatal estrogen exposure, causing alterations, enhanced hypothalamic suppressed female rats. Functional vitro analyses demonstrated strong repressive on UTR. Moreover, infusion juvenile period target site blockers, tailored prevent miR-30 reversed prepubertal down-regulation delayed puberty. Collectively, our data unveil novel miRNA pathway, involving prominent role puberty via repression. These findings expand current understanding basis disease states.