Forkhead 转录因子 FOXG1 是哺乳动物端脑发育的先决条件，并且是通过促进神经元和中间神经元产生来控制背侧端脑扩张的重要因素。杂合FOXG1基因突变导致 FOXG1 综合征，其特征是严重的智力障碍、运动迟缓、运动障碍和癫痫。患者的神经影像学研究揭示了持续的特征，包括小头畸形、胼胝体发育不全和髓鞘形成延迟。目前，对潜在病理生理学的调查研究仅依赖于小鼠模型，并表明 FOXG1 靶基因的去抑制可能导致神经元过早分化，代价是祖细胞池、模式和迁移缺陷以及皮质-皮质投射的形成受损。这在多大程度上概括了FOXG1单倍体不足患者的神经发育病理生理学仍然是一个悬而未决的问题。为了弥补这一差距，我们对两个胎儿病例进行了神经病理学分析FOXG1过早终止密码子突变在妊娠晚期因小头畸形和胼胝体发育不全而中断。在这些胎儿中，我们观察到皮质分层缺陷和神经元密度降低，主要影响通常会引起皮质皮质和半球间轴突投影的 II、III 和 V 层。GABA 能中间神经元在皮质板和持续萌发区的数量也减少了。此外，与年龄匹配的对照大脑相比，我们观察到更多的 PDGFRα 阳性少突胶质细胞前体细胞和更少的 Olig2 阳性前少突胶质细胞，认为少突胶质细胞谱系的延迟产生和分化导致髓鞘形成延迟。这些发现提供了对 FOXG1 综合征人类病理生理学的重要见解。

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