title: Akt-independent GSK3 inactivation downstream of PI3K signaling regulates mammalian axon regeneration.
abstract: Inactivation of glycogen synthase kinase 3 (GSK3) has been shown to mediate axon growth during development and regeneration. Phosphorylation of GSK3 by the kinase Akt is well known to be the major mechanism by which GSK3 is inactivated. However, whether such regulatory mechanism of GSK3 inactivation is used in neurons to control axon growth has not been directly studied. Here by using GSK3 mutant mice, in which GSK3 is insensitive to Akt-mediated inactivation, we show that sensory axons regenerate normally in vitro and in vivo after peripheral axotomy. We also find that GSK3 in sensory neurons of the mutant mice is still inactivated in response to peripheral axotomy and such inactivation is required for sensory axon regeneration. Lastly, we provide evidence that GSK3 activity is negatively regulated by PI3K signaling in the mutant mice upon peripheral axotomy, and the PI3K-GSK3 pathway is functionally required for sensory axon regeneration. Together, these results indicate that in response to peripheral nerve injury GSK3 inactivation, regulated by an alternative mechanism independent of Akt-mediated phosphorylation, controls sensory axon regeneration.
authors: Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States; Department of Orthopaedic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, China.
authors: Bo-Yin
authors: BY
authors: Zhang
authors: Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors: Saijilafu
authors: Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors: Chang-Mei
authors: CM
authors: Liu
authors: Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors: Rui-Ying
authors: RY
authors: Wang
authors: Department of Orthopaedic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, China.
authors: Qingsan
authors: Q
authors: Zhu
authors: Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States.
authors: Zhongxian
authors: Z
authors: Jiao
authors: Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States; The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States. Electronic address: fzhou4@jhmi.edu.
authors: Feng-Quan
authors: FQ
authors: Zhou
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009416:Nerve Regeneration; D059348:Peripheral Nerve Injuries / Q000378:metabolism* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: Axon regeneration; GSK3 signaling; In vivo electroporation; PI3K signaling