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- Title
Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3.
- Authors
Heras, Violeta; Sangiao-Alvarellos, Susana; Manfredi-Lozano, Maria; Sanchez-Tapia, María 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
- Abstract
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. The microRNA miR-30 suppresses the expression of Mkrn3 (a known repressor of puberty) in the hypothalamus by binding to a highly conserved region of its 3' untranslated region, representing a novel mechanism for finely modulating the tempo of puberty.
- Subjects
PUBERTY; BINDING sites; FUNCTIONAL analysis; DISEASE progression; MICRORNA
- Publication
PLoS Biology, 2019, Vol 17, Issue 11, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3000532