title: Cdk5-mediated phosphorylation of Axin directs axon formation during cerebral cortex development.
abstract: Axon formation is critical for the establishment of connections between neurons, which is a prerequisite for the development of neural circuitry. Kinases such as cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase-3β (GSK-3β), have been implicated to regulate axon outgrowth. Nonetheless, the in vivo roles of these kinases in axon development and the underlying signaling mechanisms remain essentially unknown. We report here that Cdk5 is important for axon formation in mouse cerebral cortex through regulating the functions of axis inhibitor (Axin), a scaffold protein of the canonical Wnt pathway. Knockdown of Axin in utero abolishes the formation and projection of axons. Importantly, Axin is phosphorylated by Cdk5, and this phosphorylation facilitates the interaction of Axin with GSK-3β, resulting in inhibition of GSK-3β activity and dephosphorylation of its substrate collapsin response mediator protein-2 (CRMP-2), a microtubule-associated protein. Specifically, both phosphorylation of Axin and its interaction with GSK-3β are critically required for axon formation in mouse cortex development. Together, our findings reveal a new regulatory mechanism of axon formation through Cdk5-dependent phosphorylation of Axin.
authors.affiliation: Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
authors.forename: Wei-Qun
authors.initials: WQ
authors.lastname: Fang
authors.forename: Jacque P K
authors.initials: JP
authors.lastname: Ip
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Yu Pong
authors.initials: YP
authors.lastname: Ng
authors.forename: Sheng-Cai
authors.initials: SC
authors.lastname: Lin
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Amy K Y
authors.initials: AK
authors.lastname: Fu
authors.forename: Nancy Y
authors.initials: NY
authors.lastname: Ip
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D002540:Cerebral Cortex / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D055785:Gene Knockdown Techniques / Q000379:methods; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D060466:Axin Protein; D036341:Intercellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C095114:collapsin response mediator protein-2; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3