The impact of FOXG1 on human cortico-cerebral astrogenesis

Foxg1 is a transcription factor gene involved in key steps of early corticocerebral development, including specification of the telencephalic and cortical fields, tuning of proliferation/differentiation kinetics, radial migration of projection neurons and laminar specification of them. Its allele dosage is crucial. Hemizygosity for Foxg1 and duplication of it result into two devastating nosological entities, namely the Rett and West syndromes, respectively. We previously showed that Foxg1, like its Drosophila m. ortholog sloppy paired, also antagonizes gliogenesis. Aim of this study was to investigate the role of FOXG1 in human cortex, in particular the early commitment of pallial precursor cells towards glial fates and subsequent implementation of the astrocytic differentiation program. For this purpose, we followed two approaches: (1) we modulated the expression of Foxg1 by lentiviral vectors in human pallial precursor cells originating from the embryonic W8 of the gene in early commitment and astrocytic differentiation; (2) we generated human induced pluripotent stem cells (hiPSCs) starting from somatic non neural cells of patients affected by the FOXG1 linked variant of the WS, then we forced these iPSCs to differentiate to cortical precursors to score their histogenetic properties. We found that Foxg1 overexpression in pallial precursor cells reduces their astroglial output, in particular S100β+population. An opposite effect is elicited by halving Foxg1 gene dosage. Moreover Foxg1 overexpression also interferes with selected aspects of late astrocyte differentiation, possibly jeopardizing anti-excitotoxic capability of these cells. These findings may help to reconstruct the molecular logic underlying normal articulation of astrogenesis. Moreover they provide useful hints about pathogenetic mechanisms leading to neurological disorders triggered by altered FOXG1 dosage.