PAK3 activation promotes the tangential to radial migration switch of cortical interneurons by increasing leading process dynamics and disrupting cell polarity.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
07 Mar 2024
07 Mar 2024
Historique:
received:
11
08
2023
accepted:
07
02
2024
revised:
31
01
2024
medline:
8
3
2024
pubmed:
8
3
2024
entrez:
7
3
2024
Statut:
aheadofprint
Résumé
Mutations of PAK3, a p21-activated kinase, are associated in humans with cognitive deficits suggestive of defective cortical circuits and with frequent brain structural abnormalities. Most human variants no longer exhibit kinase activity. Since GABAergic interneurons express PAK3 as they migrate within the cortex, we here examined the role of PAK3 kinase activity in the regulation of cortical interneuron migration. During the embryonic development, cortical interneurons migrate a long distance tangentially and then re-orient radially to settle in the cortical plate, where they contribute to cortical circuits. We showed that interneurons expressing a constitutively kinase active PAK3 variant (PAK3-ca) extended shorter leading processes and exhibited unstable polarity. In the upper cortical layers, they entered the cortical plate and extended radially oriented processes. In the deep cortical layers, they exhibited erratic non-processive migration movements and accumulated in the deep pathway. Pharmacological inhibition of PAK3 kinase inhibited the radial migration switch of interneurons to the cortical plate and reduced their accumulation in the deep cortical layers. Interneurons expressing a kinase dead PAK3 variant (PAK3-kd) developed branched leading processes, maintained the same polarity during migration and exhibited processive and tangentially oriented movements in the cortex. These results reveal that PAK3 kinase activity, by promoting leading process shortening and cell polarity changes, inhibits the tangential processive migration of interneurons and favors their radial re- orientation and targeting to the cortical plate. They suggest that patients expressing PAK3 variants with impaired kinase activity likely present alterations in the cortical targeting of their GABAergic interneurons.
Identifiants
pubmed: 38454080
doi: 10.1038/s41380-024-02483-y
pii: 10.1038/s41380-024-02483-y
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Fondation pour la Recherche Médicale (Foundation for Medical Research in France)
ID : Thesis Fellowship
Organisme : Ministère de la Santé et des Services sociaux (Ministery of Health and Social Services)
ID : Thesis fellowship
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : MIGRACIL
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : MIGRACIL
Organisme : Brain and Behavior Research Foundation (Brain & Behavior Research Foundation)
ID : Young Researcher Fellowship
Informations de copyright
© 2024. The Author(s).
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