The Role of MeCP2 and FoxG1 in Embryonic Cortical Development: Implications for Autism Spectrum Disorders

Abstract

Autism spectrum disorders (ASDs) represent a group of neurodevelopmental conditions characterized by impaired social interactions, communication difficulties, and repetitive behaviors. While the etiologies of ASDs are complex and heterogeneous, mounting evidence points to disrupted cortical development as a fundamental pathogenic mechanism. Two genes that play critical roles in cortical development and have been implicated in ASDs are FOXG1 and MECP2. Mutations in FOXG1 cause a rare neurodevelopmental disorder known as FOXG1 syndrome, which presents with autistic features, microcephaly, and severe intellectual disability. Similarly, mutations in MECP2 cause Rett syndrome, another severe neurodevelopmental disorder that also includes autistic features. Despite the phenotypic overlap between FOXG1 and Rett syndromes, the molecular relationship between FOXG1 and MECP2 during cortical development remains poorly understood. Both genes encode transcriptional regulators expressed in the developing and mature brain, suggesting they may coordinate gene expression programs essential for proper neurodevelopment. However, their precise temporal and spatial expression patterns, target genes, and functional interactions are largely unknown. This thesis aims to elucidate the developmental relationship between FOXG1 and MECP2 in the context of cortical development and ASD pathogenesis. Using a combination of immunohistochemistry, genomic analyses, and cellular models, the following aspects were investigated:

The spatiotemporal expression patterns of FOXG1 and MECP2 in the developing mouse cortex Potential reciprocal regulation between these factors at the transcriptional level The impact of FOXG1 and MECP2 deficiency on gene expression programs in neural progenitor cells and early differentiating neurons Overlapping molecular pathways dysregulated in both conditions that may underlie shared phenotypic features Through these integrated analyses, this thesis aims to provide novel insights into FOXG1 and MECP2 function during the critical period of cortical development and identify convergent molecular mechanisms that may inform the understanding of ASD pathogenesis. Ultimately, this work may uncover new therapeutic targets and strategies for these devastating neurodevelopmental disorders.