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TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway.

Authors
  • Falace, Antonio
  • Buhler, Emmanuelle
  • Fadda, Manuela
  • Watrin, Françoise
  • Lippiello, Pellegrino
  • Pallesi-Pocachard, Emilie
  • Baldelli, Pietro
  • Benfenati, Fabio
  • Zara, Federico
  • Represa, Alfonso
  • Fassio, Anna
  • Cardoso, Carlos
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Publication Date
Feb 11, 2014
Volume
111
Issue
6
Pages
2337–2342
Identifiers
DOI: 10.1073/pnas.1316294111
PMID: 24469796
Source
Medline
Keywords
License
Unknown

Abstract

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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