Netrin-1/DCC signaling in commissural axon guidance requires cell-autonomous expression of heparan sulfate
Netrin-1/DCC signaling in commissural axon guidance requires cell-autonomous expression of heparan sulfate
复制标题
DOI：
10.1523/jneurosci.0700-07.2007
复制
发表时间：
2007-04-18
影响因子：
5.3
通讯作者：
Yamaguchi, Yu
中科院分区：
文献类型：
--
作者：
Matsumoto, Yoshihiro;Irie, Fumitoshi;Yamaguchi, Yu
越来越多的证据表明，硫酸乙酰肝素(HS)在各种轴突引导过程中发挥着重要作用。然而，这些观察并没有说明HS是细胞自主地作为轴突辅助受体所必需的，还是作为一个环境因素来调节引导分子在生长轴突所处的地形中的定位。在这里，我们证明了netrin-1介导的连合轴突引导需要体内连合神经元中HS的细胞自主表达。我们使用WNT1-Cre转基因来驱动脊髓背部对Ext1的区域特异性消融，Ext1编码一种合成HS所必需的酶。值得注意的是，WNT1-Cre介导的Ext1消融导致了与Netrin-1缺陷和DCC(在结直肠癌中缺失)缺陷小鼠相似的连合轴突通路缺陷。无论是缺失Ext1的脊髓背侧外植体，还是HS表达被去除的野生型外植体，都不能延长轴突对netrin-1的反应。Netrin-1和DCC下游的细胞内信号在Ext1缺陷的连合神经元和去掉HS的DCC转基因HEK293T细胞中是缺陷的。这些结果表明，HS的表达对于这些神经元转导netrin-1信号是必不可少的，从而为HS在netrin-1/DCC介导的轴突引导中发挥细胞自主作用提供了证据。
There is increasing evidence that heparan sulfate (HS) plays an essential role in various axon guidance processes. These observations, however, have not addressed whether HS is required cell autonomously as an axonal coreceptor or as an environmental factor that modulates the localization of guidance molecules in the terrain in which growing axons navigate. Here we demonstrate that netrin-1-mediated commissural axon guidance requires cell-autonomous expression of HS in commissural neurons in vivo. We used the Wnt1-Cre transgene to drive region-specific ablation of Ext1, which encodes an enzyme essential for HS synthesis, in the dorsal part of the spinal cord. Remarkably, Wnt1-Cre-mediated ablation of Ext1 causes commissural axon pathfinding defects that share similarities with those of Netrin-1-deficient and DCC ( deleted in colorectal cancer)-deficient mice. Neither Ext1-deficient dorsal spinal cord explants nor wild-type explants in which HS expression was ablated could extend axons in response to netrin-1. Intracellular signaling downstream of netrin-1 and DCC was defective in Ext1-deficient commissural neurons and in DCC-transfected HEK293T cells from which HS was removed. These results demonstrate that the expression of HS by commissural neurons is essential for these neurons to transduce netrin-1 signals, thus providing evidence for a cell-autonomous role of HS in netrin-1/DCC-mediated axon guidance.