TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway.
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.
Department of Experimental Medicine, University of Genova, 16132 Genova, Italy.
Antonio
A
Falace
Emmanuelle
E
Buhler
Manuela
M
Fadda
Françoise
F
Watrin
Pellegrino
P
Lippiello
Emilie
E
Pallesi-Pocachard
Pietro
P
Baldelli
Fabio
F
Benfenati
Federico
F
Zara
Alfonso
A
Represa
Anna
A
Fassio
Carlos
C
Cardoso
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D003712:Dendrites / Q000502:physiology; D020690:GTPase-Activating Proteins; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid / Q000378:metabolism; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology*; D051381:Rats; D013569:Synapses / Q000378:metabolism
D000089982:ADP-Ribosylation Factor 6; D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C552551:TBC1D24 protein, human; D018698:Glutamic Acid; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715349:Arf6 protein, rat
RNA interference; dendritogenesis; epileptic encephalopathies; gene; synaptogenesis