Heras, VioletaSangiao-Alvarellos, SusanaManfredi-Lozano, MariaSanchez-Tapia, María JRuiz-Pino, FranciscoRoa, JuanLara-Chica, MaribelMorrugares-Carmona, RosarioJouy, NathalieAbreu, Ana PPrevot, VincentBelsham, DeniseVazquez, Maria JCalzado, Marco APinilla, LeonorGaytan, FranciscoLatronico, Ana CKaiser, Ursula BCastellano, Juan MTena-Sempere, Manuel2023-02-082023-02-082019-10-25Heras 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):e3000532http://hdl.handle.net/10668/14651Mkrn3, 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/RatsSequence analysis, DNASexual maturationUbiquitin-protein ligasesAnimalsBinding sitesCell lineFemaleGene expression regulation, developmentalHypothalamusMaleMicroRNAsresearch article31697675open accessHipotálamoLínea celularMicroARNsRegulación del desarrollo de la expresión génicaSitios de unión10.1371/journal.pbio.30005321545-7885PMC6863565https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3000532&type=printablehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863565/pdf