Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
24
07
2020
accepted:
12
02
2021
revised:
12
01
2021
pubmed:
18
3
2021
medline:
27
1
2022
entrez:
17
3
2021
Statut:
ppublish
Résumé
E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for autism spectrum disorder (ASD) and developmental delay (DD). To investigate how Cul3 mutations impact brain development, we generated a haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of embryonic, early postnatal and adult brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development.
Identifiants
pubmed: 33727673
doi: 10.1038/s41380-021-01052-x
pii: 10.1038/s41380-021-01052-x
pmc: PMC8443683
mid: NIHMS1673612
doi:
Substances chimiques
Cullin Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3586-3613Subventions
Organisme : NINDS NIH HHS
ID : P30 NS047101
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH108528
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH100175
Pays : United States
Organisme : NIMH NIH HHS
ID : R21 MH104766
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH109885
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH119746
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH113715
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023100
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH105524
Pays : United States
Informations de copyright
© 2021. The Author(s).
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