title: Spatially coordinated kinase signaling regulates local axon degeneration.
abstract: In addition to being a hallmark of neurodegenerative disease, axon degeneration is used during development of the nervous system to prune unwanted connections. In development, axon degeneration is tightly regulated both temporally and spatially. Here, we provide evidence that degeneration cues are transduced through various kinase pathways functioning in spatially distinct compartments to regulate axon degeneration. Intriguingly, glycogen synthase kinase-3 (GSK3) acts centrally, likely modulating gene expression in the cell body to regulate distally restricted axon degeneration. Through a combination of genetic and pharmacological manipulations, including the generation of an analog-sensitive kinase allele mutant mouse for GSK3β, we show that the β isoform of GSK3, not the α isoform, is essential for developmental axon pruning in vitro and in vivo. Additionally, we identify the dleu2/mir15a/16-1 cluster, previously characterized as a regulator of B-cell proliferation, and the transcription factor tbx6, as likely downstream effectors of GSK3β in axon degeneration.
authors.affiliation: Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Chen
authors.forename: Janice A
authors.initials: JA
authors.lastname: Maloney
authors.forename: Dara Y
authors.initials: DY
authors.lastname: Kallop
authors.forename: Jasvinder K
authors.initials: JK
authors.lastname: Atwal
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tam
authors.forename: Kristin
authors.initials: K
authors.lastname: Baer
authors.forename: Holger
authors.initials: H
authors.lastname: Kissel
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Kaminker
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lewcock
authors.forename: Robby M
authors.initials: RM
authors.lastname: Weimer
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Watts
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism*; D002478:Cells, Cultured; D018274:Electroporation; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D005838:Genotype; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047468:Immunoprecipitation; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology* / Q000517:prevention & control; D020932:Nerve Growth Factor / Q000172:deficiency; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000502:physiology; D010770:Phosphotransferases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D000097573:Red Fluorescent Protein
chemical_list: D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D020932:Nerve Growth Factor; D009419:Nerve Tissue Proteins; D010770:Phosphotransferases; D034741:RNA, Small Interfering; D000097573:Red Fluorescent Protein; C485184:enhanced green fluorescent protein; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse; C448021:glycogen synthase kinase 3 alpha