Draxin Inhibits Axonal Outgrowth through the Netrin Receptor DCC
Draxin Inhibits Axonal Outgrowth through the Netrin Receptor DCC
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DOI：
10.1523/jneurosci.0943-11.2011
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发表时间：
2011-09-28
影响因子：
5.3
通讯作者：
Tanaka, Hideaki
中科院分区：
文献类型：
--
作者：
Ahmed, Giasuddin;Shinmyo, Yohei;Tanaka, Hideaki
DraXin是最近发现的轴突引导蛋白，对前脑连合的形成是必不可少的，并且可以介导Netrin刺激的脊髓连合轴突的排斥。在这里，我们报道了DRAXIN结合了多个Netrin受体：DCC(在结直肠癌中缺失)、新生素、UNC5s(H1、H2、H3)和DSCAM(唐氏综合征细胞黏附分子)。由于DRAXIN和DCC敲除基因在前脑联合形成中表现出相似的表型，我们在这里展示了DRAXIN/DCC相互作用的功能重要性。DraXin与Netrin受体DCC有亚纳摩尔亲和力，位于DCC区域，不同于其Netrin结合域。在体外，与野生型小鼠外植体的轴突相比，DCC基因敲除小鼠的皮质和嗅球外植体的轴突生长明显受到德拉新的抑制。此外，与野生型小鼠相比，在缺乏DCC的皮质神经元中，德拉辛反应的生长锥塌陷在很大程度上被消除了。在活体内，DRAXIN/DCC小鼠的双异种小鼠显示出明显高于单异种小鼠的胼胝体完全发育不全。这些结果证实DCC在轴突生长和引导中是网织蛋白和德拉辛的会聚受体。
Draxin, a recently identified axon guidance protein, is essential for the formation of forebrain commissures, and can mediate repulsion of netrin-stimulated spinal commissural axons. Here, we report that draxin binds multiple netrin receptors: DCC (deleted in colorectal cancer), Neogenin, UNC5s (H1, H2, H3), and DSCAM (Down's syndrome cell adhesion molecule). Since draxin and Dcc knockouts showed similar phenotype in forebrain commissures formation, we show here the functional importance of draxin/DCC interaction. Draxin interacts with subnanomolar affinity to the netrin receptor DCC, in a region of DCC distinct from its netrin-binding domain. In vitro, neurite outgrowth from cortical and olfactory bulb explants of Dcc knock-out mice is significantly less inhibited by draxin, when compared with neurites from explants of wild-type mice. Furthermore, in comparison with wild-type mice, the growth cone collapse in response to draxin is largely abolished in Dcc-deficient cortical neurons. In vivo, double heteros of draxin/Dcc mice show markedly higher frequency of complete agenesis of corpus callosum than either of the single hetero. These results identify DCC as a convergent receptor for netrin and draxin in axon growth and guidance.