Journal
EMBO JOURNAL
Volume 39, Issue 13, Pages -Publisher
WILEY
DOI: 10.15252/embj.2019104163
Keywords
BBSOAS; cell cycle dynamics; cortical folding; neurodevelopmental disease; COUP-TFI
Categories
Funding
- ERA-NET Neuron II grant (ImprovVision) [ANR-15-NEUR-0002-04]
- Jerome Lejeune Foundation [199162]
- Investments for the Future LabEx SIGNALIFE [ANR-11-LABX-0028-01]
- city of Nice, France (Aides Individuelles aux Jeunes Chercheurs)
- EMBO short-term fellowship (STF) [8035]
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The relationships between impaired cortical development and consequent malformations in neurodevelopmental disorders, as well as the genes implicated in these processes, are not fully elucidated to date. In this study, we report six novel cases of patients affected by BBSOAS (Boonstra-Bosch-Schaff optic atrophy syndrome), a newly emerging rare neurodevelopmental disorder, caused by loss-of-function mutations of the transcriptional regulatorNR2F1. Young patients withNR2F1haploinsufficiency display mild to moderate intellectual disability and show reproducible polymicrogyria-like brain malformations in the parietal and occipital cortex. Using a recently established BBSOAS mouse model, we found thatNr2f1regionally controls long-term self-renewal of neural progenitor cells via modulation of cell cycle genes and key cortical development master genes, such asPax6. In the human fetal cortex, distinct NR2F1 expression levels encompass gyri and sulci and correlate with local degrees of neurogenic activity. In addition, reduced NR2F1 levels in cerebral organoids affect neurogenesis and PAX6 expression. We proposeNR2F1as an area-specific regulator of mouse and human brain morphology and a novel causative gene of abnormal gyrification.
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