Spatially Coordinated Kinase Signaling Regulates Local Axon Degeneration
Spatially Coordinated Kinase Signaling Regulates Local Axon Degeneration
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DOI：
10.1523/jneurosci.2039-12.2012
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发表时间：
2012-09-26
影响因子：
5.3
通讯作者：
Watts, Ryan J.
中科院分区：
文献类型：
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作者：
Chen, Mark;Maloney, Janice A.;Watts, Ryan J.
除了是神经退行性疾病的标志外，轴突变性在神经系统发育期间用于修剪不需要的连接。在发育过程中，轴突变性在时间和空间上都受到严格的调控。在这里，我们提供的证据表明，变性线索转导通过各种激酶途径在空间上不同的隔间，以调节轴突变性。有趣的是，糖原合成酶激酶-3（GSK 3）起中枢作用，可能调节细胞体中的基因表达以调节远端限制性轴突变性。通过遗传学和药理学操作的组合，包括生成一个类似物敏感的激酶等位基因突变小鼠的GSK 3 β，我们表明，β亚型的GSK 3，而不是α亚型，是必不可少的体外和体内发育轴突修剪。此外，我们确定了dleu 2/mir 15 a/16-1簇，以前的特点是作为一个调节器的B细胞增殖，和转录因子tbx 6，作为可能的下游效应的GSK 3 β在轴突变性。
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 GSK3 beta, we show that the beta isoform of GSK3, not the alpha 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 GSK3 beta in axon degeneration.