Human neuropathology confirms projection neuron and interneuron defects and delayed oligodendrocyte production and maturation in FOXG1 syndrome

The Forkhead transcription factor FOXG1 is a prerequisite for telencephalon development in mammals and an essential controlling expansion of the dorsal by promoting neuron interneuron production. Heterozygous gene mutations cause syndrome characterized severe intellectual disability, motor delay, dyskinetic movements epilepsy. Neuroimaging studies patients disclose constant features including microcephaly, corpus callosum dysgenesis delayed myelination. Currently, investigative research on underlying pathophysiology relies mouse models only indicates that de-repression target genes may premature neuronal differentiation at expense progenitor pool, patterning migration defects with impaired formation cortico-cortical projections. It remains open question to which extent this recapitulates neurodevelopmental FOXG1-haploinsufficient patients. To close gap, we performed neuropathological analyses two foetal cases stop codon interrupted during third trimester pregnancy microcephaly dysgenesis. In these foetuses, observed cortical lamination decreased density mainly affecting layers II, III V normally give rise inter-hemispheric axonal GABAergic interneurons were also reduced number plate persisting germinative zones. Additionally, more numerous PDGFR?-positive oligodendrocyte precursor cells fewer Olig2-positive pre-oligodendrocytes compared age-matched control brains, arguing production lineage leading These findings provide key insights into human syndrome.