ESPEYB20 5. Puberty Basic Research (6 abstracts)
5.11. Dicer ablation in Kiss1 neurons impairs puberty and fertility preferentially in female mice
Roa J , Ruiz-Cruz M , Ruiz-Pino F , Onieva R , Vazquez MJ , Sanchez-Tapia MJ , Ruiz-Rodriguez JM , Sobrino V , Barroso A , Heras V , Velasco I , Perdices-Lopez C , Ohlsson C , Avendaño MS , Prevot V , Poutanen M , Pinilla L , Gaytan F & Tena-Sempere M
Nat Commun. 2022;13(1):4663.PMID: 35945211. https://www.nature.com/articles/s41467-022-32347-4
Brief summary: A newly developed mouse model of congenital ablation of Dicer in kisspeptin neurons was used to identify a role for miRNAs in kisspeptin neuron activity and control of reproduction.
The last few years have seen a shift in paradigm with the discovery of epigenetic mechanisms regulating GnRH neuron activity and thus puberty and reproduction. In particular, miRNAs appear to play a crucial role in the maturation and function of the hypothalamic-pituitary-gonadal axis. While MKRN3 (1) and GnRH (2) expression are known to be regulated by miRNA, such regulation of Kisspeptin had not been explored.
DICER is an RNAse enzyme, which is necessary for the maturation of all miRNAs and the formation of the RNA-induced silencing complex (3). In order to study miRNA regulatory pathways in kisspeptin neurons, the authors developed a mouse model in which Dicer was selectively ablated in kiss1 neurons (KiDKO mice). Such congenital ablation led to hypogonadotropic hypogonadism in adult male and female mice. Adult KiDKO males and females showed undetectable levels of Kiss1 expression in the arcuate nucleus and KO females also showed no detectable levels in the AVPV. KiDKO mice showed a significant LH response to GnRH and kisspeptin, indicating that the functional defect was in kisspeptin neurons. Interestingly, KiDKO males and females showed normal puberty timing as well as normal gonadotropin and sex steroid levels prepubertally. Males were fertile at 2 months of age but not at 4 months, while females did not start ovulation and were infertile at 2 and 4 months of age. As miRNA are mostly gene silencers, it appears that miRNAs probably decreased the expression of Kiss1 repressors, as hinted by increased expression of mkrn3, eap1 and Cbx7 in isolated kisspeptin neurons from KiDKO mice. Notably, Kiss1 expression was largely conserved around minipuberty, which suggests that conservation of kisspeptin neuronal populations during minipuberty is sufficient to activate puberty.
In conclusion, the newly developed model of congenital ablation of Dicer illustrates the essential role of miRNA in Kisspeptin neurons for the completion of puberty and maintenance of fertility in both sexes. In contrast, miRNAs in Kisspeptin neurons are dispensable for kisspeptin neuron survival and pubertal onset. These data suggest that abnormal miRNA biogenesis could explain some forms of late onset hypogonadotropic hypogonadism.
References: 1. 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. Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3. PLoS Biol. 2019;17:e3000532. 2. Messina, A, Langlet F, Chachlaki K, Roa J, Rasika S, Jouy N, Gallet S, Gaytan F, Parkash J, Tena-Sempere M, Giacobini P, Prevot V. A microRNA switch regulates the rise in hypothalamic GnRH production before puberty. Nat. Neurosci. 2016;19:835–844. 3. Hammond, S.M. Dicing and slicing: the coremachinery of the RNA interference pathway. FEBS Lett. 2005;579:5822–5829.
Article tools
My recent searches
My recently viewed abstracts
Authors
ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more