NR2F1 regulates regional progenitor dynamics in the mouse neocortex and cortical gyrification in BBSOAS patients.
NR2F1/COUP-TFI
BBSOAS
cell cycle dynamics
cortical folding
neurodevelopmental disease
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
01 07 2020
01 07 2020
Historique:
received:
02
12
2019
revised:
01
04
2020
accepted:
15
04
2020
pubmed:
3
6
2020
medline:
7
4
2021
entrez:
3
6
2020
Statut:
ppublish
Résumé
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 regulator NR2F1. Young patients with NR2F1 haploinsufficiency 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 that Nr2f1 regionally controls long-term self-renewal of neural progenitor cells via modulation of cell cycle genes and key cortical development master genes, such as Pax6. 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 propose NR2F1 as an area-specific regulator of mouse and human brain morphology and a novel causative gene of abnormal gyrification.
Identifiants
pubmed: 32484994
doi: 10.15252/embj.2019104163
pmc: PMC7327499
doi:
Substances chimiques
COUP Transcription Factor I
0
NR2F1 protein, human
0
Nr2f1 protein, mouse
0
PAX6 Transcription Factor
0
PAX6 protein, human
0
Pax6 protein, mouse
0
Banques de données
GEO
['GSE146595']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e104163Subventions
Organisme : Agence Nationale de la Recherche (ANR)
ID : ANR-15-NEUR-0002-04
Organisme : Agence Nationale de la Recherche (ANR)
ID : ANR-11-LABX-0028-01
Organisme : European Molecular Biology Organization (EMBO)
ID : STF#8035
Organisme : Ville de Nice - Aides Individuelles aux Jeunes Chercheurs
Organisme : Fondation Jérôme Lejeune
ID : 199162
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
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