Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3
: Violeta Heras, Susana Sangiao-Alvarellos, Maria Manfredi-Lozano, María J. Sanchez-Tapia, Francisco Ruiz-Pino, Juan Roa, Maribel Lara-Chica, Rosario Morrugares-Carmona, 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
Publisher: PUBLIC LIBRARY SCIENCE
: 2019
: PLoS Biology
: PLOS BIOLOGY
: PLOS BIOL
: ARTN e3000532
: 17
: 11
: 24
: 1544-9173
: 1545-7885
DOI: https://doi.org/10.1371/journal.pbio.3000532
: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000532
: https://research.utu.fi/converis/portal/detail/Publication/45140280
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.
