The p21-activated kinase is required for neuronal migration in the cerebral cortex.
The normal formation and function of the mammalian cerebral cortex depend on the positioning of its neurones, which occurs in a highly organized, layer-specific manner. The correct morphology and movement of neurones rely on synchronized regulation of their actin filaments and microtubules. The p21-activated kinase (Pak1), a key cytoskeletal regulator, controls neuronal polarization, elaboration of axons and dendrites, and the formation of dendritic spines. However, its in vivo role in the developing nervous system is unclear. We have utilized in utero electroporation into mouse embryo cortices to reveal that both loss and gain of Pak1 function affect radial migration of projection neurones. Overexpression of hyperactivated Pak1 predominantly caused neurones to arrest in the intermediate zone (IZ) with apparently misoriented and disorganized leading projections. Loss of Pak1 disrupted the morphology of migrating neurones, which accumulated in the IZ and deep cortical layers. Unexpectedly, a significant number of neurones with reduced Pak1 expression aberrantly entered into the normally cell-sparse marginal zone, suggesting their inability to cease migrating that may be due to their impaired dissociation from radial glia. Our findings reveal the in vivo importance of temporal and spatial regulation of the Pak1 kinase during key stages of cortical development.
Causeret
Frédéric
F
Department of Cellular and Molecular Neuroscience, Imperial College School of Medicine, London, UK.
Terao
Mami
M
Jacobs
Tom
T
Nishimura
Yoshiaki V
YV
Yanagawa
Yuchio
Y
Obata
Kunihiko
K
Hoshino
Mikio
M
Nikolic
Margareta
M
D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000201:enzymology*; D002522:Chlorocebus aethiops; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D051379:Mice; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*
D008565:Membrane Proteins; D054462:p21-Activated Kinases