Cell-surface heparan sulfate is involved in the repulsive guidance activities of Slit2 protein

Hu, Huaiyu

doi:10.1038/89482

Cited by 190 publications

(153 citation statements)

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“…These two modes of action are not entirely mutually exclusive. Increasing data indicate that some axon guidance molecules also bind HS and require HS to exert their functions (Hu, 2001;Inatani et al, 2003;Kantor et al, 2004) (for review, see Lee and Chien, 2004;Holt and Dickson, 2005). Considering that axon guidance occurs in highly defined topological contexts, it is important to determine which mode of HS action is used in the function of these molecules.…”

Section: Discussionmentioning

confidence: 99%

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

Matsumoto¹,

Irie²,

Inatani³

et al. 2007

J. Neurosci.

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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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Section: Discussionmentioning

confidence: 99%

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

Matsumoto¹,

Irie²,

Inatani³

et al. 2007

J. Neurosci.

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“…Thus, it seems likely that a coreceptor is required to transmit SLIT binding into ROBO4 activation. In some contexts, ROBO1 may fulfill this function (5), whereas in other contexts it may be served by receptors such as a Syndecan (11,12).…”

Section: Discussionmentioning

confidence: 99%

“…ROBO1, which binds directly to SLITs, has been shown to promote endothelial cell motility, either alone (2,6,10) or as a heterodimeric partner with ROBO4 (5,9). In contrast, ROBO4 binds SLITs at either very low affinity or not at all and likely requires a coreceptor, such as ROBO1 or a Syndecan, to signal (5,11,12). ROBO4 has been assigned the repellent functions of SLITs (7,8) and, more recently, an alternative role in countering the effects of vascular endothelial growth factor (VEGF) to provide vascular stabilization (13,14).…”

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confidence: 99%

Vascular Robo4 restricts proangiogenic VEGF signaling in breast

Marlow

Binnewies

Sorensen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Formation of the vascular system within organs requires the balanced action of numerous positive and negative factors secreted by stromal and epithelial cells. Here, we used a genetic approach to determine the role of SLITs in regulating the growth and organization of blood vessels in the mammary gland. We demonstrate that vascularization of the gland is not affected by loss of Slit expression in the epithelial compartment. Instead, we identify a stromal source of SLIT, mural cells encircling blood vessels, and show that loss of Slit in the stroma leads to elevated blood vessel density and complexity. We examine candidate SLIT receptors, Robo1 and Robo4, and find that increased vessel angiogenesis is phenocopied by loss of endothelial-specific Robo4, as long as it is combined with the presence of an angiogenic stimulus such as preneoplasia or pregnancy. In contrast, loss of Robo1 does not affect blood vessel growth. The enhanced growth of blood vessels in Robo4 −/− endothelium is due to activation of vascular endothelial growth factor (VEGF)-R2 signaling through the Src and FAK kinases. Thus, our studies present a genetic dissection of SLIT/ROBO signaling during organ development. We identify a stromal, rather than epithelial, source of SLITs that inhibits blood vessel growth by signaling through endothelial ROBO4 to down-regulate VEGF/ VEGFR2 signaling.angiogenesis | ROBO | SLIT | mammary gland | organogenesis

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“…Thus, biochemical experiments have shown that Slits bind the heparan sulfate proteoglycan glypican-1 (Liang et al, 1999;Ronca et al, 2001). Heparan sulfate enhances the affinity of Slit2 for Robo1 receptors in vitro, and removal of cell surface heparan sulfate by heparinase III treatment or addition of saturating amounts of heparan sulfate abolishes the repulsive activity of Slit2 toward olfactory bulb axons in explant cultures (Hu, 2001). Moreover, nervous system-specific conditional mutants for EXT1, a glycosyltransferase enzyme required for the synthesis of heparan sulfate, display guidance defects at the optic chiasm that are similar to those found in Slit1;Slit2 double mutants Inatani et al, 2003).…”

Section: Interaction Of Slit/robo Signaling With Other Moleculesmentioning

confidence: 99%

Robo1 and Robo2 Cooperate to Control the Guidance of Major Axonal Tracts in the Mammalian Forebrain

López‐Bendito¹,

Flames²,

Ma³

et al. 2007

J. Neurosci.

205

209

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The function of the nervous system depends on the precision of axon wiring during development. Previous studies have demonstrated that Slits, a family of secreted chemorepellent proteins, are crucial for the proper development of several major forebrain tracts. Mice deficient in Slit2 or, even more so, in both Slit1 and Slit2 have defects in multiple axonal pathways, including corticofugal, thalamocortical, and callosal connections. In the spinal cord, members of the Robo family of proteins help mediate the function of Slits, but the relative contribution of these receptors to the guidance of forebrain projections remains to be determined. In the present study, we addressed the function of Robo1 and Robo2 in the guidance of forebrain projections by analyzing Robo1-, Robo2-, and Robo1;Robo2-deficient mice. Mice deficient in Robo2 and, more dramatically, in both Robo1 and Robo2, display prominent axon guidance errors in the development of corticofugal, thalamocortical, and corticocortical callosal connections. Our results demonstrate that Robo1 and Robo2 mostly cooperate to mediate the function of Slit proteins in guiding the major forebrain projections.

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Cell-surface heparan sulfate is involved in the repulsive guidance activities of Slit2 protein

Cited by 190 publications

References 50 publications

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

Vascular Robo4 restricts proangiogenic VEGF signaling in breast

Robo1 and Robo2 Cooperate to Control the Guidance of Major Axonal Tracts in the Mammalian Forebrain

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