Facilitation of axon outgrowth via a Wnt5a-CaMKK-CaMKIα pathway during neuronal polarization.
Facilitation of axon outgrowth via a Wnt5a-CaMKK-CaMKIα pathway during neuronal polarization.
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DOI：
10.1186/s13041-016-0189-3
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发表时间：
2016-01-16
期刊：
影响因子：
3.6
通讯作者：
Bito H
中科院分区：
文献类型：
--
作者：
Horigane S;Ageta-Ishihara N;Kamijo S;Fujii H;Okamura M;Kinoshita M;Takemoto-Kimura S;Bito H
Wnt5A最初被认为是连合轴突的引导信号，它激活了对皮质轴突形态发生至关重要的非规范途径。这一事件背后的分子信号级联仍然不清楚。通过对急性胚胎皮质脑片进行钙离子成像，我们测试了已有原始轴突的径向迁移的皮质兴奋性神经元是否对Wnt5a敏感。虽然WNT5a只在中间带(IZ)的未成熟神经元中诱发短暂的钙瞬变，但WNT5a诱导的钙振荡在迁移到皮质板(CP)的神经元中持续存在。我们想知道神经元极化过程中早期的Wnt5a-Ca~(2+)信号是否具有形态发生的结果。在从圆形向极化形状转变的过程中，WNT5a给未成熟培养的皮质神经元特异性地促进轴突生长，但不促进树突生长。药物和遗传抑制CaMKK-CaMKIα通路可阻断WNT5a诱导的轴突延长，而挽救CaMKIα敲除神经元中的CaMKIα可恢复WNT5a介导的轴突生长。这项研究表明，Wnt5a在神经元形态发生时间窗口激活了钙信号，此时轴突生长是关键的促进因素。此外，在神经元极化过程中，CaMKK-CaMKIα级联对于WNT5a的轴突生长效应是必需的。本文的在线版本(doi：10.1186/s13041-0160189-3)包含补充材料，授权用户可以使用。
Wnt5a, originally identified as a guidance cue for commissural axons, activates a non-canonical pathway critical for cortical axonal morphogenesis. The molecular signaling cascade underlying this event remains obscure. Through Ca2+ imaging in acute embryonic cortical slices, we tested if radially migrating cortical excitatory neurons that already bore primitive axons were sensitive to Wnt5a. While Wnt5a only evoked brief Ca2+ transients in immature neurons present in the intermediate zone (IZ), Wnt5a-induced Ca2+ oscillations were sustained in neurons that migrated out to the cortical plate (CP). We wondered whether this early Wnt5a-Ca2+ signaling during neuronal polarization has a morphogenetic consequence. During transition from round to polarized shape, Wnt5a administration to immature cultured cortical neurons specifically promoted axonal, but not dendritic, outgrowth. Pharmacological and genetic inhibition of the CaMKK-CaMKIα pathway abolished Wnt5a-induced axonal elongation, and rescue of CaMKIα in CaMKIα-knockdown neurons restored Wnt5a-mediated axon outgrowth. This study suggests that Wnt5a activates Ca2+ signaling during a neuronal morphogenetic time window when axon outgrowth is critically facilitated. Furthermore, the CaMKK-CaMKIα cascade is required for the axonal growth effect of Wnt5a during neuronal polarization. The online version of this article (doi:10.1186/s13041-016-0189-3) contains supplementary material, which is available to authorized users.