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The Journal of Neuroscience, April 18, 2007, 27(16):4342-4350; doi:10.1523/JNEUROSCI.0700-07.2007

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Development/Plasticity/Repair
Netrin-1/DCC Signaling in Commissural Axon Guidance Requires Cell-Autonomous Expression of Heparan Sulfate

Yoshihiro Matsumoto,¹ Fumitoshi Irie,^1,2 Masaru Inatani,¹ Marc Tessier-Lavigne,³ and Yu Yamaguchi^1,2

¹Developmental Neurobiology and ²Glycobiology Programs, Burnham Institute for Medical Research, La Jolla, California 92037, and ³Genentech, South San Francisco, California 94080

Correspondence should be addressed to Yu Yamaguchi, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. Email: yyamaguchi{at}burnham.org

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.

Key words: heparan sulfate; Ext1; netrin-1; DCC; spinal cord; axon guidance

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Received Sept. 8, 2006; accepted March 12, 2007.

Correspondence should be addressed to Yu Yamaguchi, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037. Email: yyamaguchi{at}burnham.org

This article has been cited by other articles:

				F. Irie, M. Okuno, K. Matsumoto, E. B. Pasquale, and Y. Yamaguchi Heparan sulfate regulates ephrin-A3/EphA receptor signaling PNAS, August 26, 2008; 105(34): 12307 - 12312. [Abstract] [Full Text] [PDF]

				C. L. R. Merry and C. M. Ward A sugar rush for developmental biology Development, April 15, 2008; 135(8): 1389 - 1393. [Abstract] [Full Text] [PDF]

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