Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 6, Pages 2337-2342Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1316294111
Keywords
dendritogenesis; synaptogenesis; epileptic encephalopathies; gene; RNA interference
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Funding
- Italian Ministry of Health Progetto Giovani
- Fondazione Mariani
- Institut National de la Sante et de la Recherche Medicale
- European Union [2006-037315]
- Else Kroner-Fresenius Foundation [2010_A145]
- Consorzio Italiano Biotecnologie
- European Molecular Biology Organization short-term fellowship
- Boehringer travel grant
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Alterations in the formation of brain networks are associated with several neurodevelopmental disorders. Mutations in TBC1 domain family member 24 (TBC1D24) are responsible for syndromes that combine cortical malformations, intellectual disability, and epilepsy, but the function of TBC1D24 in the brain remains unknown. We report here that in utero TBC1D24 knockdown in the rat developing neocortex affects the multipolar-bipolar transition of neurons leading to delayed radial migration. Furthermore, we find that TBC1D24-knockdown neurons display an abnormal maturation and retain immature morphofunctional properties. TBC1D24 interacts with ADP ribosylation factor (ARF)6, a small GTPase crucial for membrane trafficking. We show that in vivo, overexpression of the dominant-negative form of ARF6 rescues the neuronal migration and dendritic outgrowth defects induced by TBC1D24 knockdown, suggesting that TBC1D24 prevents ARF6 activation. Overall, our findings demonstrate an essential role of TBC1D24 in neuronal migration and maturation and highlight the physiological relevance of the ARF6-dependent membrane-trafficking pathway in brain development.
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