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

Matsumoto, Yoshihiro; Irie, Fumitoshi; Inatani, Masaru; Tessier‐Lavigne, Marc; Yamaguchi, Yu

doi:10.1523/jneurosci.0700-07.2007

Cited by 77 publications

(68 citation statements)

References 49 publications

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“…In the cases of FGF2 and netrin-1, HS acts as an essential coreceptor, for ligand interaction with the cognate receptors that activate downstream signaling (38,39). Our analysis of mutant limb buds and micromass cultures revealed that the intensity of BMP signaling is somewhat impaired, but not entirely abolished, in the absence of HS.…”

Section: Discussionmentioning

confidence: 81%

Conditional Ablation of the Heparan Sulfate-synthesizing Enzyme Ext1 Leads to Dysregulation of Bone Morphogenic Protein Signaling and Severe Skeletal Defects

Matsumoto¹,

Matsumoto²,

Irie³

et al. 2010

Journal of Biological Chemistry

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Increasing evidence indicates that heparan sulfate (HS) is an integral component of many morphogen signaling pathways. However, its mechanisms of action appear to be diverse, depending on the type of morphogen and the developmental contexts. To define the function of HS in skeletal development, we conditionally ablated Ext1, which encodes an essential glycosyltransferase for HS synthesis, in limb bud mesenchyme using the Prx1-Cre transgene. These conditional Ext1 mutant mice display severe limb skeletal defects, including shortened and malformed limb bones, oligodactyly, and fusion of joints. In developing limb buds of mutant mice, chondrogenic differentiation of mesenchymal condensations is delayed and impaired, whereas the area of differentiation is diffusely expanded. Correspondingly, the distribution of both bone morphogenic protein (BMP) signaling domains and BMP2 immunoreactivity in the mutant limb mesenchyme is broadened and diffuse. In micromass cultures, chondrogenic differentiation of mutant chondrocytes is delayed, and the responsiveness to exogenous BMPs is attenuated. Moreover, the segregation of the pSmad1/5/8-expressing chondrocytes and fibronectin-expressing perichondrium-like cells surrounding chondrocyte nodules is disrupted in mutant micromass cultures. Together, our results show that HS is essential for patterning of limb skeletal elements and that BMP signaling is one of the major targets for the regulatory role of HS in this developmental context.Endochondral ossification, one of the two major modes of bone formation, is responsible for the formation of limb bones (1, 2). Within developing limb buds, mesenchymal progenitor cells form condensations, in which chondrocytes and perichondrial cells differentiate in the core and in the periphery, respectively. Hypertrophic chondrocytes direct perichondrial cell differentiation into osteoblasts, whereas perichondrial cell signaling regulates proliferation and hypertrophic changes in chondrocytes. These differentiation processes are governed by an intricate signaling network involving secreted morphogens and growth factors, including bone morphogenic proteins (BMPs), 3 fibroblast growth factors, Indian hedgehog (Ihh), parathyroid hormone-related hormone, and WNT proteins (1, 3).Heparan sulfate proteoglycans (HSPGs) play critical roles in many developmental processes. Many growth factors and morphogens, including those that play a role in skeletal development, exhibit affinities for the heparan sulfate (HS) chains of HSPGs (4, 5). The physiological importance of HS in skeletal development is also illustrated by the presence of a human bone disorder caused by genetic defects in enzymes involved in HS synthesis. Multiple hereditary exostoses (MHE) is an autosomal dominant disorder characterized by the formation of multiple osteochondromas as well as by limb bone deformity and is caused by hemizygous mutation of Ext1, which encodes a glycosyltransferase essential for HS synthesis (6, 7). Mutations of Ext2, which encodes an EXT1-related protein that for...

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Section: Discussionmentioning

confidence: 81%

Conditional Ablation of the Heparan Sulfate-synthesizing Enzyme Ext1 Leads to Dysregulation of Bone Morphogenic Protein Signaling and Severe Skeletal Defects

Matsumoto¹,

Matsumoto²,

Irie³

et al. 2010

Journal of Biological Chemistry

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“…This has been suggested to be an effect of a transient reduction in HS-dependent fibroblast growth factor signaling during embryogenesis. Moreover, heparan sulfate and chondroitin sulfate proteoglycans (HSPGs and CSPGs, respectively) serve different functions during brain development, with CSPGs inhibiting and HSPGs promoting axon extension (50). GPC1 is exclusively substituted with HS, whereas GPC5, for example, can exist as an HS CS/DS (where DS is dermatan sulfate) hybrid.…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of N-Glycosylated Human Glypican-1 Core Protein

Svensson

Awad

Håkansson

et al. 2012

Journal of Biological Chemistry

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Background:The glypican family of cell-surface proteoglycans regulates growth factor signaling during development through their core proteins and heparan sulfate chains. Results: The crystal structure of N-glycosylated human glypican-1 is described. Conclusion:The structure reveals the complete disulfide bond arrangement for the conserved Cys residues in glypicans. Significance: Increased structural knowledge of glypicans will help elucidate their important functions in shaping animal development.

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“…Signals generated by the engagement of ephrin ligands to Eph receptors generally result in repulsive responses, such as retraction of the cell periphery and cell rounding, and growth cone collapse in neurons. These repulsive responses are thought to be the basis for the function of the ephrin-Eph system in axon guidance.The function of many important morphogens and guidance molecules has been shown to involve accessory molecules as coreceptors or as a mechanism to control the topological distribution of the guidance molecules (7,8,(12)(13)(14). Curiously, there is little information on whether ephrin-Eph signaling is influenced by heparan sulfate or other accessory regulatory molecules.…”

mentioning

confidence: 99%

“…The function of many important morphogens and guidance molecules has been shown to involve accessory molecules as coreceptors or as a mechanism to control the topological distribution of the guidance molecules (7,8,(12)(13)(14). Curiously, there is little information on whether ephrin-Eph signaling is influenced by heparan sulfate or other accessory regulatory molecules.…”

mentioning

confidence: 99%

“…Molecules involved in axon pathfinding, such as netrin-1, Slit, and semaphorins, are other major targets of regulation by heparan sulfate (4). We have used genetic ablation of the Ext1 gene, which encodes a glycosyltransferase essential for heparan sulfate synthesis (5,6), to demonstrate the physiological significance of the interactions of some of these molecules with heparan sulfate (7)(8)(9).…”

mentioning

confidence: 99%

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Heparan sulfate regulates ephrin-A3/EphA receptor signaling

Irie¹,

Okuno²,

Matsumoto³

et al. 2008

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

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Increasing evidence indicates that many signaling pathways involve not only ligands and receptors but also various types of coreceptors and matrix components as additional layers of regulation. Signaling by Eph receptors and their ephrin ligands plays a key role in a variety of biological processes, such as axon guidance and topographic map formation, synaptic plasticity, angiogenesis, and cancer. Little is known about whether the ephrin-Eph receptor signaling system is subject to such additional layers of regulation. Here, we show that ephrin-A3 binds to heparan sulfate, and that the presence of cell surface heparan sulfate is required for the full biological activity of ephrin-A3. Among the ephrins tested, including ephrin-A1, -A2, -A5, -B1, and -B2, only ephrin-A3 binds heparin or heparan sulfate. Ephrin-A3-dependent EphA receptor activation is reduced in mutant cells that are defective in heparan sulfate synthesis, in wild-type cells from which cell surface heparan sulfate has been removed, and in the hippocampus of conditional knockout mice defective in heparan sulfate synthesis. Ephrin-A3-dependent cell rounding is impaired in CHO cells lacking heparan sulfate, and cortical neurons lacking heparan sulfate exhibit impaired growth cone collapse. In contrast, cell rounding and growth cone collapse in response to ephrin-A5, which does not bind heparan sulfate, are not affected by the absence of heparan sulfate. These results show that heparan sulfate modulates ephrin/Eph signaling and suggest a physiological role for heparan sulfate proteoglycans in the regulation of ephrin-A3-dependent biological processes.proteoglycan ͉ cell adhesion ͉ growth cone collapse H eparan sulfate is a class of sulfated glycosaminoglycans. It occurs as heparan sulfate proteoglycans, in which one or more heparan sulfate chains are covalently attached to a variety of core proteins (1). Heparin is a specialized form of heparan sulfate synthesized exclusively by connective tissue mast cells, whereas heparan sulfate is expressed in many cell types. The negatively charged sulfate groups of heparan sulfate mediate interactions with a variety of proteins. Increasing evidence indicates that heparan sulfate acts as an integral component of a number of morphogen and growth factor signaling pathways by interacting with these molecules. For example, fibroblast growth factors, Wnts, Sonic hedgehog, bone morphogenetic proteins, and neuregulins bind to heparan sulfate and are functionally modulated by it (2, 3). Molecules involved in axon pathfinding, such as netrin-1, Slit, and semaphorins, are other major targets of regulation by heparan sulfate (4). We have used genetic ablation of the Ext1 gene, which encodes a glycosyltransferase essential for heparan sulfate synthesis (5, 6), to demonstrate the physiological significance of the interactions of some of these molecules with heparan sulfate (7-9).The Eph receptors form the largest family of receptor tyrosine kinases. Together with their membrane-bound ligands, the ephrins, they are involved in b...

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

Cited by 77 publications

References 49 publications

Conditional Ablation of the Heparan Sulfate-synthesizing Enzyme Ext1 Leads to Dysregulation of Bone Morphogenic Protein Signaling and Severe Skeletal Defects

Conditional Ablation of the Heparan Sulfate-synthesizing Enzyme Ext1 Leads to Dysregulation of Bone Morphogenic Protein Signaling and Severe Skeletal Defects

Crystal Structure of N-Glycosylated Human Glypican-1 Core Protein

Heparan sulfate regulates ephrin-A3/EphA receptor signaling

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