Dataset Information

Cdk5-mediated phosphorylation of RapGEF2 controls neuronal migration in the developing cerebral cortex.

ABSTRACT: During cerebral cortex development, pyramidal neurons migrate through the intermediate zone and integrate into the cortical plate. These neurons undergo the multipolar-bipolar transition to initiate radial migration. While perturbation of this polarity acquisition leads to cortical malformations, how this process is initiated and regulated is largely unknown. Here we report that the specific upregulation of the Rap1 guanine nucleotide exchange factor, RapGEF2, in migrating neurons corresponds to the timing of this polarity transition. In utero electroporation and live-imaging studies reveal that RapGEF2 acts on the multipolar-bipolar transition during neuronal migration via a Rap1/N-cadherin pathway. Importantly, activation of RapGEF2 is controlled via phosphorylation by a serine/threonine kinase Cdk5, whose activity is largely restricted to the radial migration zone. Thus, the specific expression and Cdk5-dependent phosphorylation of RapGEF2 during multipolar-bipolar transition within the intermediate zone are essential for proper neuronal migration and wiring of the cerebral cortex.

SUBMITTER: Ye T

PROVIDER: S-EPMC4164783 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Cdk5-mediated phosphorylation of RapGEF2 controls neuronal migration in the developing cerebral cortex.

Ye Tao T Ip Jacque P K JP Fu Amy K Y AK Ip Nancy Y NY

Nature communications 20140905

During cerebral cortex development, pyramidal neurons migrate through the intermediate zone and integrate into the cortical plate. These neurons undergo the multipolar-bipolar transition to initiate radial migration. While perturbation of this polarity acquisition leads to cortical malformations, how this process is initiated and regulated is largely unknown. Here we report that the specific upregulation of the Rap1 guanine nucleotide exchange factor, RapGEF2, in migrating neurons corresponds to ...[more]

PMID: 25189171

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Project description:The actin cytoskeleton is crucial for neuronal migration in the mammalian developing cerebral cortex. The adaptor protein Drebrin-like (Dbnl) plays important roles in reorganization of the actin cytoskeleton, dendrite formation, and endocytosis by interacting with F-actin, cobl, and dynamin. Although Dbnl is known to be expressed in the brain, the functions of this molecule during brain development are largely unknown. In this study, to examine the roles of Dbnl in the developing cerebral cortex, we conducted experiments using mice of both sexes with knockdown of Dbnl, effected by in utero electroporation, in the migrating neurons of the embryonic cortex. Time-lapse imaging of the Dbnl-knockdown neurons revealed that the presence of Dbnl is a prerequisite for appropriate formation of processes in the multipolar neurons in the multipolar cell accumulation zone or the deep part of the subventricular zone, and for neuronal polarization and entry into the cortical plate. We found that Dbnl knockdown decreased the amount of N-cadherin protein expressed on the plasma membrane of the cortical neurons. The defect in neuronal migration caused by Dbnl knockdown was rescued by moderate overexpression of N-cadherin and αN-catenin or by transfection of the phospho-mimic form (Y337E, Y347E), but not the phospho-resistant form (Y337F, Y347F), of Dbnl. These results suggest that Dbnl controls neuronal migration, neuronal multipolar morphology, and cell polarity in the developing cerebral cortex via regulating N-cadherin expression.SIGNIFICANCE STATEMENT Disruption of neuronal migration can cause neuronal disorders, such as lissencephaly and subcortical band heterotopia. During cerebral cortical development, the actin cytoskeleton plays a key role in neuronal migration; however, the mechanisms of regulation of neuronal migration by the actin cytoskeleton still remain unclear. Herein, we report that the novel protein Dbnl, an actin-binding protein, controls multiple events during neuronal migration in the developing mouse cerebral cortex. We also showed that this regulation is mediated by phosphorylation of Dbnl at tyrosine residues 337 and 347 and αN-catenin/N-cadherin, suggesting that the Dbnl-αN-catenin/N-cadherin pathway is important for neuronal migration in the developing cortex.

Dataset Information

Cdk5-mediated phosphorylation of RapGEF2 controls neuronal migration in the developing cerebral cortex.

Publications

Cdk5-mediated phosphorylation of RapGEF2 controls neuronal migration in the developing cerebral cortex.

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