The first objective of our work was to provide a detailed description of MECP2 expression patterns and timetable in the developing cortex of human and non-human primates.

Secondly, we focused on the effects of MECP2 overexpression and downmodulation in cortical progenitors that generate infragranular layer neurons (layers VI-V) in the macaque fetal cortex.

The spatiotemporal expression of MECP2 was investigated using immunostaining of parasagittal sections of fetal macaque brains at different developmental stages and Western Blot analyses. Additionally, the MECP2 expression profile was further explored in human forebrain organoids. Up and down regulation of MECP2 expression in organotypic cultures of the macaque fetal cortex was carried-out using an EGFP retroviral infection approach that targets cycling progenitors in an unbiased manner. This method enables the labeling of cycling progenitors across multiple cell divisions, allowing long-term observation of their morphology and behavior using two-photon video microscopy (Betizeau et al., 2013).

We report a rostro-caudal gradient of increasing MECP2 expression reminiscent of the rostro-caudal maturation gradient of cortical areas, as well as an apical-basal gradient in the developing cortical wall.

We next report the consequences of MECP2 modulation on the proliferative behavior of cortical progenitors. We observed significant alterations in the cell-cycle parameters of apical progenitors following MECP2 overexpression, affecting their proliferation kinetics, division mode, and cellular features such as interkinetic nuclear migration in the ventricular zone. Additionally, we describe the consequences of MECP2 modulation on the dynamics of radial migration of newborn neurons and their maturation.

Our results suggest that proper MECP2 levels are critical during the early stages of corticogenesis in primates for the appropriate production rate of cortical neurons, as well as during later stages for their final maturation.