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.
