Back to Search
Start Over
Human neuropathology confirms projection neuron and interneuron defects and delayed oligodendrocyte production and maturation in FOXG1 syndrome.
- Source :
-
European journal of medical genetics [Eur J Med Genet] 2021 Sep; Vol. 64 (9), pp. 104282. Date of Electronic Publication: 2021 Jul 17. - Publication Year :
- 2021
-
Abstract
- 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.<br /> (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Aborted Fetus metabolism
Aborted Fetus pathology
Adult
Agenesis of Corpus Callosum pathology
Axons metabolism
Brain embryology
Brain metabolism
Brain pathology
Codon, Nonsense
Female
Forkhead Transcription Factors metabolism
GABAergic Neurons metabolism
GABAergic Neurons pathology
Humans
Interneurons metabolism
Interneurons pathology
Microcephaly pathology
Myelin Sheath metabolism
Nerve Tissue Proteins metabolism
Neurodevelopmental Disorders pathology
Oligodendroglia metabolism
Pedigree
Pregnancy
Syndrome
Agenesis of Corpus Callosum genetics
Axons pathology
Forkhead Transcription Factors genetics
Microcephaly genetics
Nerve Tissue Proteins genetics
Neurodevelopmental Disorders genetics
Neurogenesis
Oligodendroglia pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1878-0849
- Volume :
- 64
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- European journal of medical genetics
- Publication Type :
- Academic Journal
- Accession number :
- 34284163
- Full Text :
- https://doi.org/10.1016/j.ejmg.2021.104282