Dicer ablation in Kiss1 neurons impairs puberty and fertility preferentially in female mice

• Published in: Nature communications Vol. 13; no. 1; p. 4663
• Main Authors: Roa, Juan, Ruiz-Cruz, Miguel, Ruiz-Pino, Francisco, Onieva, Rocio, Vazquez, Maria J, Sanchez-Tapia, Maria J, Ruiz-Rodriguez, Jose M, Sobrino, Veronica, Barroso, Alexia, Heras, Violeta, Velasco, Inmaculada, Perdices-Lopez, Cecilia, Ohlsson, Claes, Avendaño, Maria Soledad, Prevot, Vincent, Poutanen, Matti, Pinilla, Leonor, Gaytan, Francisco, Tena-Sempere, Manuel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 09.08.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Ablation; Biosynthesis; Females; Fertility; Hypogonadism; Hypothalamus; Juveniles; Kiss1 protein; MicroRNAs; miRNA; Neurons; Puberty; Regulatory mechanisms (biology); Repressors; Ribonucleic acid; RNA; Sex differences; Subpopulations
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32347-4

Abstract Kiss1 neurons, producing kisspeptins, are essential for puberty and fertility, but their molecular regulatory mechanisms remain unfolded. Here, we report that congenital ablation of the microRNA-synthesizing enzyme, Dicer, in Kiss1 cells, causes late-onset hypogonadotropic hypogonadism in both sexes, but is compatible with pubertal initiation and preserved Kiss1 neuronal populations at the infantile/juvenile period. Yet, failure to complete puberty and attain fertility is observed only in females. Kiss1-specific ablation of Dicer evokes disparate changes of Kiss1-cell numbers and Kiss1 /kisspeptin expression between hypothalamic subpopulations during the pubertal-transition, with a predominant decline in arcuate-nucleus Kiss1 levels, linked to enhanced expression of its repressors, Mkrn3, Cbx7 and Eap1. Our data unveil that miRNA-biosynthesis in Kiss1 neurons is essential for pubertal completion and fertility, especially in females, but dispensable for initial reproductive maturation and neuronal survival in both sexes. Our results disclose a predominant miRNA-mediated inhibitory program of repressive signals that is key for precise regulation of Kiss1 expression and, thereby, reproductive function.