ESPEYB17 7. Puberty Basic Science (8 abstracts)
7.12. Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3
Heras V , Sangiao-Alvarellos S , Manfredi-Lozano M , Sanchez-Tapia MJ , Ruiz- Pino F , Roa J , Lara-Chica M , Morrugares-Carmona R , Jouy N , Abreu AP , Prevot V , Belsham D , Vazquez MJ , Calzado MA , Pinilla L , Gaytan F , Latronico AC , Kaiser UB , Castellano JM & Tena-Sempere M
To read the full abstract: PLoS biology vol. 17,11 e3000532. 7 Nov. 2019. doi: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000532
This study unravels the role of the miR-30/Mkrn3 pathway in the hypothalamic regulation of puberty
Puberty onset is triggered by a hypothalamic network of interconnected genes regulated by a complex transcriptional network (1). Among transcriptional factors, Mkrn3, a maternally imprinted gene encoding the makorin RING-finger protein-3, has been recently identified as an essential inhibitory component of the gene network governing puberty. Mutations in Mknr3 were found to cause precocious puberty in boys and girls (2) and its expression decreases throughout sexual maturation (3). However, the molecular mechanisms of Mkrn3 regulation of puberty are still unknown. Recently, microRNAs (miRNAs), short noncoding RNAs, have emerged as relevant regulatory elements of puberty (4).
Using miRNA-target prediction bioinformatic tools, these authors identified that the 3’UTR of Mkrn3 includes a binding site for the miR-30 family. Analyzing mRNA expression in the hypothalamus, they observed that miR-30b expression increases during peri-puberty while the level of Mkrn3 decreases. The physiological role of the miR-30/Mkrn3 pathway in the control of puberty was attested by blocking miR-30 binding to the 3’UTR of Mkrn3. This blockage attenuated the decrease in hypothalamic Mkrn3 during peri-puberty and significantly delayed puberty onset. Thus, the miR-30/Mkrn3 pathway is added to the newly identified sets of ‘repressors of repressors’ involved in the multilayered control of puberty, such as the Lin28/let-7 system (5), and the miR-200/Zeb1 and miR-155/Cebpb tandems (4), which control GnRH expression.
References:
1. Lomniczi A, Wright H, Castellano JM, Sonmez K, Ojeda SR. (2013). A system biology approach to identify regu- latory pathways underlying the neuroendocrine control of female puberty in rats and nonhuman pri- mates. Horm Behav 64:175–18.
2. Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, et al. (2013). Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med 368:2467–2475.
3. Liu H, Kong X, Chen F. (2017) Mkrn3 functions as a novel ubiquitin E3 ligase to inhibit Nptx1 during puberty initiation. Oncotarget 8:85102–85109.
4. Messina A, Langlet F, Chachlaki K, Roa J, Rasika S, Jouy N, et al. (2016). A microRNA switch regulates the rise in hypothalamic GnRH production before puberty. Nat Neurosci 19:835–844.
5. Sangiao-Alvarellos S, Manfredi-Lozano M, Ruiz-Pino F, Navarro VM, Sanchez-Garrido MA, Leon S, et al. (2013). Changes in hypothalamic expression of the Lin28/let-7 system and related microRNAs during postnatal maturation and after experimental manipulations of puberty. Endocrinology 154:942–955.
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ESPE Yearbook of Paediatric Endocrinology
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