Sex-Dimorphic Behavioral Alterations and Altered Neurogenesis in U12 Intron Splicing-Defective <i>Zrsr1</i> Mutant Mice

• Main Authors: Francisco Alén, Isabel Gómez-Redondo, Patricia Rivera, Juan Suárez, Priscila Ramos-Ibeas, Eva Pericuesta, Raul Fernández-González, Serafín Perez-Cerezales, Keiko Horiuchi, Laura Orio, Fernando Rodriguez de Fonseca, Alfonso Gutiérrez-Adán
• Format: Article
• Language: English
• Published: MDPI AG 2019-07-01
• Series: International Journal of Molecular Sciences
• Subjects: <i>Zrsr1</i>; U12 introns; hypothalamus; behavior; social interaction; neurogenesis; cell proliferation
• Online Access: https://www.mdpi.com/1422-0067/20/14/3543

Mutant mice with respect to the splicing factor <i>Zrsr1</i> present altered spermatogenesis and infertility. To investigate whether <i>Zrsr1</i> is involved in the homeostatic control that the hypothalamus exerts over reproductive functions, we first analyzed both differential gene and isoform expression and alternative splicing alterations in <i>Zrsr1</i> mutant (<i>Zrsr1^mu</i>) hypothalamus; second, we analyzed the spontaneous and social behavior of <i>Zrsr1^mu</i> mice; and third, we analyzed adult cell proliferation and survival in the <i>Zrsr1^mu</i> hypothalamus. The <i>Zrsr1^mu</i> hypothalamus showed altered expression of genes and isoforms related to the glutathione metabolic process, synaptonemal complex assembly, mRNA transport, and altered splicing events involving the enrichment of U12-type intron retention (IR). Furthermore, increased IR in U12-containing genes related with the prolactin, progesterone, and gonadotropin-releasing hormone (GnRH) reproductive signaling pathway was observed. This was associated with a hyperactive phenotype in both males and females, with an anxious phenotype in females, and with increased social interaction in males, instead of the classical aggressive behavior. In addition, <i>Zrsr1^mu</i> females but not males exhibited reduced cell proliferation in both the hypothalamus and the subventricular zone. Overall, these results suggest that <i>Zrsr1</i> expression and function are relevant to organization of the hypothalamic cell network controlling behavior.