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

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Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3.
PLOS Biology ( IF 7.8 ) Pub Date : 2019-11-07 , DOI: 10.1371/journal.pbio.3000532
Violeta Heras ₁ , Susana Sangiao-Alvarellos ₂ , Maria Manfredi-Lozano ₁ , María J Sanchez-Tapia ₁ , Francisco Ruiz-Pino ₁ , Juan Roa ₁ , Maribel Lara-Chica ₁ , Rosario Morrugares-Carmona ₁ , Nathalie Jouy ₃ , Ana P Abreu ₄ , Vincent Prevot ₃ , Denise Belsham ₅ , Maria J Vazquez _{1,

6} , Marco A Calzado ₁ , Leonor Pinilla _{1,

6} , Francisco Gaytan _{1,

6} , Ana C Latronico ₇ , Ursula B Kaiser ₄ , Juan M Castellano _{1,

6} , Manuel Tena-Sempere _{1,

6,

8}

Affiliation

Department of Cell Biology, Physiology and Immunology, University of Córdoba & Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC)/Hospital Universitario Reina Sofia, Cordoba, Spain.
Department of Medicine, Faculty of Health Sciences, University of A Coruña, A Coruña, Spain, Instituto de Investigación Biomédica (INIBIC), University Hospital A Coruña, A Coruña, Spain.
Jean-Pierre Aubert Research Center, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Inserm, UMR-S 1172, Lille, France.
Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
Department of Physiology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada.
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Córdoba, Spain.
Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, LIM 42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil.
FiDiPro Program, Institute of Biomedicine, University of Turku, Kiinamyllynkatu, Turku, Finland.

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.

中文翻译：

下丘脑 miR-30 通过抑制青春期抑制因子 Mkrn3 来调节青春期开始。

Mkrn3 是编码 makorin RING-finger protein-3 的母体印记基因，最近已成为推定的青春期阻遏物，人类 MKRN3 突变引起的中枢性早熟证明了这一点。然而，这一关键监管行动的分子基础在很大程度上仍未得到探索。我们在此报告了 microRNA，miR-30，在其 3' UTR 的高度保守区域具有三个结合位点，作为 Mkrn3 的阻遏物来控制青春期发病。在大鼠出生后成熟期间，下丘脑 miR-30b 表达增加，而 Mkrn3 mRNA 和蛋白质含量减少。新生儿雌激素暴露导致青春期改变，增强下丘脑 Mkrn3 并抑制雌性大鼠中 miR-30b 的表达。体外功能分析表明 miR-30b 对 Mkrn3 3' UTR 具有强烈的抑制作用。而且，在青少年时期中央输注靶点阻滞剂，专门用于防止 miR-30 与 Mkrn3 3' UTR 结合，逆转下丘脑 Mkrn3 蛋白的青春期前下调并延迟女性青春期。总的来说，我们的数据揭示了一种新的下丘脑 miRNA 通路，涉及 miR-30，在通过 Mkrn3 抑制控制青春期方面具有重要作用。这些发现扩展了我们目前对青春期分子基础及其疾病状态的理解。

更新日期：2019-12-03

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