Spatially coordinated kinase signaling regulates local axon degeneration

• Published in: The Journal of neuroscience Vol. 32; no. 39; pp. 13439 - 13453
• Main Authors: Chen, Mark, Maloney, Janice A, Kallop, Dara Y, Atwal, Jasvinder K, Tam, Stephen J, Baer, Kristin, Kissel, Holger, Kaminker, Joshua S, Lewcock, Joseph W, Weimer, Robby M, Watts, Ryan J
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 26.09.2012
• Subjects: Animals; Animals, Newborn; Axons - metabolism; Cells, Cultured; Electroporation; Embryo, Mammalian; Enzyme Inhibitors - pharmacology; Female; Ganglia, Spinal - cytology; Gene Expression Profiling - methods; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - genetics; Gene Expression Regulation, Developmental - physiology; Genotype; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Green Fluorescent Proteins - genetics; Hippocampus - cytology; Humans; Immunoprecipitation; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Male; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; MAP Kinase Signaling System - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation - genetics; Nerve Degeneration - drug therapy; Nerve Degeneration - enzymology; Nerve Degeneration - pathology; Nerve Degeneration - prevention & control; Nerve Growth Factor - deficiency; Nerve Tissue Proteins - metabolism; Neurons - pathology; Oligonucleotide Array Sequence Analysis; Organ Culture Techniques; Phosphorylation - physiology; Phosphotransferases - metabolism; Red Fluorescent Protein; Retinal Ganglion Cells - metabolism; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Transfection
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/jneurosci.2039-12.2012

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.