title: GSK3 controls axon growth via CLASP-mediated regulation of growth cone microtubules.
abstract: Suppression of glycogen synthase kinase 3 (GSK3) activity in neurons yields pleiotropic outcomes, causing both axon growth promotion and inhibition. Previous studies have suggested that specific GSK3 substrates, such as adenomatous polyposis coli (APC) and collapsin response mediator protein 2 (CRMP2), support axon growth by regulating the stability of axonal microtubules (MTs), but the substrate(s) and mechanisms conveying axon growth inhibition remain elusive. Here we show that CLIP (cytoplasmic linker protein)-associated protein (CLASP), originally identified as a MT plus end-binding protein, displays both plus end-binding and lattice-binding activities in nerve growth cones, and reveal that the two MT-binding activities regulate axon growth in an opposing manner: The lattice-binding activity mediates axon growth inhibition induced by suppression of GSK3 activity via preventing MT protrusion into the growth cone periphery, whereas the plus end-binding property supports axon extension via stabilizing the growing ends of axonal MTs. We propose a model in which CLASP transduces GSK3 activity levels to differentially control axon growth by coordinating the stability and configuration of growth cone MTs.
authors.affiliation: Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Eun-Mi
authors.initials: EM
authors.lastname: Hur
authors.lastname: Saijilafu
authors.forename: Byoung Dae
authors.initials: BD
authors.lastname: Lee
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Xu
authors.forename: Feng-Quan
authors.initials: FQ
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001369:Axons / Q000201:enzymology / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D020439:Growth Cones / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D024462:Myosin Type II / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding
chemical_list: C506523:CLASP2 protein, mouse; C469747:Clasp protein, mouse; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D038362:Glycogen Synthase Kinase 3; D024462:Myosin Type II