Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3
Heras, Violeta; Sangiao Alvarellos, Susana; Manfredi-Lozano, Maria; Sanchez-Tapia, Maria J; Ruiz-Pino, Francisco; Roa, Juan; Lara-Chica, Maribel; Morrugares-Carmona, Rosario; Jouy, Nathalie; Abreu, Ana P; Prevot, Vincent; Belsham, Denise; Vazquez, Maria J; Calzado, Marco A; Pinilla, Leonor; Gaytan, Francisco; Latronico, Ana C; Kaiser, Ursula B; Castellano, Juan M; Tena-Sempere, Manuel
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Identificadores
URI: http://hdl.handle.net/20.500.11940/15896
PMID: 31697675
DOI: PBIOLOGY-D-19-00285
ISSN: 1544-9173
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Fecha de publicación
2019Título de revista
PLOS BIOLOGY
Tipo de contenido
Artigo
DeCS
maduración sexual | ubicuitina-proteína ligasas | microARN | animales | línea celular | análisis de secuencias | sitios de unión | hipotálamo | regulación de la expresión génica | ratasMeSH
Sexual Maturation | Ubiquitin-Protein Ligases | Rats | MicroRNAs | Cell Line | Hypothalamus | Animals | Gene Expression Regulation | Binding Sites | Sequence AnalysisResumen
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.
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