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

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Date

2019-10-25

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

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Public Library of Science
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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.

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MeSH Terms

Animals
Binding sites
Cell line
Female
Gene expression regulation, developmental
Hypothalamus
Male
MicroRNAs

DeCS Terms

Hipotálamo
Línea celular
MicroARNs
Regulación del desarrollo de la expresión génica
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Keywords

Rats, Sequence analysis, DNA, Sexual maturation, Ubiquitin-protein ligases

Citation

Heras V, Sangiao-Alvarellos S, Manfredi-Lozano M, Sanchez-Tapia MJ, Ruiz-Pino F, Roa J, et al. Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3. PLoS Biol. 2019 Nov 7;17(11):e3000532