Phenotypic characterization of a mouse model of Rett syndrome reveals pubertal dysregulation and hypothalamic-gonadal dysfunction

BackgroundMutations 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. MethodsWe first carried out a patient survey to assess pubertal timing in a sample of Spanish patients with Rett syndrome. Second, 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 measured circulating GnRH and testosterone concentrations. Finally, we analysed testosterone dependent arginine-vasopressin circuits. ResultsOur 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. Further, 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, Mecp2CD1-null male mice were found to have an increased number of GnRH neurons, but displayed lower levels of circulating reproductive hormones. Consequently, Mecp2CD1-null males have deficient testosterone-dependent arginine-vasopressin innervation. In female Mecp2CD1- heterozygous mice, we found no overall significant differences in pubertal development or GnRH neurons, albeit in a subset of mice with early neurological symptoms, we found lower body weight, and a trend to delayed vaginal opening but precocious first oestrous, attributable to variable phenotypic penetrance. ConclusionsOur 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 with an observed increase in hypothalamic GnRH neurons.