LOSS OF FUNCTION OF <EM>MECP2</EM> LEADS TO PUBERTAL DYSREGULATION AND ALTERED VASOPRESSINERGIC CIRCUITS IN A MOUSE MODEL OF RETT SYNDROME

Mutations in the X-linked MECP2 gene, encoding the epigenetic reader Methyl-CpG binding protein 2, are the main cause of Rett syndrome, a rare neurodevelopmental disorder causing severe symptoms such as intellectual disability, loss of speech and motor skills and epilepsy. Further, loss of function of MECP2 has been associated with pubertal dysregulation in humans, but the biological mechanisms leading to this remain unclear. We first carried out a patient survey to assess pubertal timing in a sample of Spanish patients with Rett syndrome; our data in patients are in agreement with previous reports showing that a subset of female patients with Rett syndrome experience a delayed timing of menarche. Second, the assessment of pubertal development in a Mecp2-mutant mouse model revealed that Mecp2-null males, which start expressing disease symptoms during pubescence, experience delayed puberty associated to lower body weight. Despite later puberty onset, Mecp2-null male mice were found to have an increased number of GnRH neurons, but displayed lower levels of circulating reproductive hormones. Consequently, Mecp2-null males have deficient testosterone-dependent vasopressinergic innervation in key nodes of the social brain. In female Mecp2-heterozygous mice, which develop the Rett-like symptomatology during adulthood, we found no overall significant differences in pubertal development. In conclusion, our data supports that MECP2 is essential for typical pubertal development, with complete loss of Mecp2 in a male murine model resulting in abnormalities of pubertal timing linked to an early onset of disease symptoms. Funded by Conselleria de Educación, Cultura y Universidades, Generalitat Valenciana (CIAICO/2023/027).