Pubertal development and hypothalamic–pituitary–gonadal axis are altered in male mice lacking <i>Mecp2</i>

Abstract Mutations in the MECP2 gene, encoding the epigenetic reader Methyl‐ CpG binding protein 2, are the main cause of Rett syndrome, a rare neurodevelopmental disorder. Besides severe symptoms such as profound intellectual disability, loss of speech and motor skills, and epilepsy, loss of function of MECP2 has been associated with pubertal dysregulation, but the biological mechanisms leading to this remain unclear. Using a mouse model of Rett, in which males are hemizygous and females heterozygous for Mecp2 loss of function mutation, we assessed the onset and progression of puberty, together with increase in body weight and onset of neurological symptoms in post‐weaning mice until puberty. In brain samples of young adult mice, we analysed hypothalamic Gonadotropin releasing hormone ( GnRH ) neurons by immunofluorescent labelling, and in plasma samples we measured circulating GnRH , LH , and testosterone concentrations. Finally, we analysed testosterone‐dependent arginine‐vasopressin circuits. In our mouse model we found delayed puberty in Mecp2 CD1 ‐null males, associated with a reduced rate of weight gain, but with puberty onset occurring at a lower body weight than in wildtype controls. Despite later puberty onset, Mecp2 CD1 ‐null male mice were found to have an increased number of GnRH neurons, but displayed lower levels of circulating reproductive hormones. Consequently, Mecp2 CD1 ‐null males have deficient testosterone‐dependent arginine‐vasopressin innervation. In female Mecp2 CD1 ‐heterozygous mice, we found no overall significant differences in pubertal development or GnRH neurons. The lack of significant alterations in females might be related to a later onset of neurological symptoms due to heterozygosity. 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 related to lower body weight, with an observed increase in hypothalamic GnRH neurons.