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Timing dependent neuronal migration is regulated by Cdk5-mediated phosphorylation of JIP1.

ABSTRACT: The mammalian brain, especially the cerebral cortex, has evolved to increase in size and complexity. The proper development of the cerebral cortex requires the coordination of several events, such as differentiation and migration, that are essential for forming a precise six-layered structure. We have previously reported that Cdk5-mediated phosphorylation of JIP1 at T205 modulates axonal out-growth. However, the spatiotemporal expression patterns and functions of these three genes (Cdk5, Cdk5r1 or p35, and Mapk8ip1 or JIP1) in distinct cell types during cortical development remain unclear. In this study, we analyzed single-cell RNA-sequencing data of mouse embryonic cortex and discovered that Cdk5, p35, and JIP1 are dynamically expressed in intermediate progenitors (IPs). Pseudotime analysis revealed that the expression of these three genes was concomitantly upregulated in IPs during neuronal migration and differentiation. By manipulating the expression of JIP1 and phospho-mimetic JIP1 using in utero electroporation, we showed that phosphorylated JIP1 at T205 affected the temporal migration of neurons.

SUBMITTER: Fei Q

PROVIDER: S-EPMC11007206 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Timing dependent neuronal migration is regulated by Cdk5-mediated phosphorylation of JIP1.

Fei Qinglin Q Im Doo Soon DS Xu Yiwen Y Huang Tianwen T Qu Dianbo D

Frontiers in cell and developmental biology 20240328

The mammalian brain, especially the cerebral cortex, has evolved to increase in size and complexity. The proper development of the cerebral cortex requires the coordination of several events, such as differentiation and migration, that are essential for forming a precise six-layered structure. We have previously reported that Cdk5-mediated phosphorylation of JIP1 at T205 modulates axonal out-growth. However, the spatiotemporal expression patterns and functions of these three genes (Cdk5, Cdk5r1 ...[more]

PMID: 38606319

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Project description:AimsChromosome 9 open reading frame 72 (C9orf72) is one of the most dazzling molecules in neurodegenerative diseases, albeit that its role in Parkinson's disease (PD) remains unknown. This article aimed to explore the potential mechanism of C9orf72 involved in the pathogenesis of PD.MethodsThe expression and phosphorylation levels of C9orf72 were examined by Western blotting, RT-PCR, and immunoprecipitation using PD models. Multiple bioinformatics software was used to predict the potential phosphorylation sites of C9orf72 by Cdk5, followed by verification of whether Cdk5-inhibitor ROSCOVITINE could reverse the degradation of C9orf72 in PD. By constructing the sh-C9orf72-knockdown adenovirus and overexpressing the FLAG-C9orf72 plasmid, the effects of C9orf72 knockdown and overexpression, respectively, were determined. A short peptide termed Myr-C9orf72 was used to verify whether interfering with Cdk5 phosphorylation at the Ser9 site of the C9orf72 protein could alleviate autophagy disorder, neuronal death, and movement disorder in PD models.ResultsThe expression level of the C9orf72 protein was significantly reduced, albeit the mRNA expression was not changed in the PD models. Moreover, the phosphorylation level was enhanced, and its reduction was mainly degraded by the ubiquitin-proteasome pathway. The key nervous system kinase Cdk5 directly phosphorylated the S9 site of the C9orf72 protein, which promoted the degradation of the C9orf72 protein. The knockdown of C9orf72 aggravated autophagy dysfunction and increased neuronal loss and motor dysfunction in substantia nigra neurons of PD mice. The overexpression of C9orf72 alleviated autophagy dysfunction in PD neurons. Specifically, interference with Cdk5 phosphorylation at the S9 site of C9orf72 alleviated autophagy dysfunction, neuronal death, and motor dysfunction mediated by C9orf72 protein degradation during PD.ConclusionsCumulatively, our findings illustrate the importance of the role of C9orf72 in the regulation of neuronal death during PD progression via the Cdk5-dependent degradation.

Dataset Information

Timing dependent neuronal migration is regulated by Cdk5-mediated phosphorylation of JIP1.

Publications

Timing dependent neuronal migration is regulated by Cdk5-mediated phosphorylation of JIP1.

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