期刊
JOURNAL OF NEUROSCIENCE
卷 27, 期 16, 页码 4342-4350出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0700-07.2007
关键词
heparan sulfate; Ext1; netrin-1; DCC; spinal cord; axon guidance
资金
- Grants-in-Aid for Scientific Research [19679008] Funding Source: KAKEN
- NICHD NIH HHS [P01 HD025938, HD25938] Funding Source: Medline
- NINDS NIH HHS [NS41332, R01 NS041332] Funding Source: Medline
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.
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