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The p21-activated kinase is required for neuronal migration in the cerebral cortex.

ABSTRACT: 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.

SUBMITTER: Causeret F

PROVIDER: S-EPMC2651475 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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The p21-activated kinase is required for neuronal migration in the cerebral cortex.

Causeret Frédéric F Terao Mami M Jacobs Tom T Nishimura Yoshiaki V YV Yanagawa Yuchio Y Obata Kunihiko K Hoshino Mikio M Nikolic Margareta M

Cerebral cortex (New York, N.Y. : 1991) 20080812 4

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 devel ...[more]

PMID: 18701438

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Project description:The collective migration of vascular endothelial cells plays important roles in homeostasis and angiogenesis. Oxygen concentration in vivo, which is lower than in the atmosphere and changes due to diseases, is a key factor affecting the cellular dynamics of vascular endothelial cells. We previously reported that hypoxic conditions promote the internalization of vascular endothelial (VE)-cadherin, a specific cell-cell adhesion molecule, and increase the velocity of the collective migration of vascular endothelial cells. However, the mechanism through which cells regulate collective migration as affected by oxygen tension is not fully understood. Here, we investigated oxygen-dependent collective migration, focusing on intracellular protein p21-activated kinase (PAK) and hypoxia-inducing factor (HIF)-1α. A monolayer of human umbilical vein vascular endothelial cells (HUVECs) was formed in a microfluidic device with controllability of oxygen tension. The HUVECs were then exposed to various oxygen conditions in a range from 0.8% to 21% O2, with or without PAK inhibition or chemical stabilization of HIF-1α. Collective cell migration was measured by particle image velocimetry with time-lapse phase-contrast microscopic images. Localizations of VE-cadherin and HIF-1α were quantified by immunofluorescent staining. The collective migration of HUVECs varied in an oxygen-dependent fashion; the migration speed was increased by hypoxic exposure down to 1% O2, while it decreased under an extremely low oxygen tension of less than 1% O2. PAK inhibition suppressed the hypoxia-induced increase of the migration speed by preventing VE-cadherin internalization into HUVECs. A decrease in the migration speed was also obtained by chemical stabilization of HIF-1α, suggesting that excessive accumulation of HIF-1α diminishes collective cell migration. These results indicate that the oxygen-dependent variation of the migration speed of vascular endothelial cells is mediated by the regulation of VE-cadherin through the PAK pathway, as well as other mechanisms via HIF-1α, especially under extreme hypoxic conditions.

Dataset Information

The p21-activated kinase is required for neuronal migration in the cerebral cortex.

Publications

The p21-activated kinase is required for neuronal migration in the cerebral cortex.

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