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Netrins and neogenin promote myotube formation.

Kang JS, Yi MJ, Zhang W, Feinleib JL, Cole F, Krauss RS - J. Cell Biol. (2004)

Bottom Line: These proteins stimulate myotube formation and enhance myogenic bHLH- and NFAT-dependent transcription.Furthermore, neogenin binds to CDO in a cis fashion, and myoblasts lacking CDO are defective in responding to recombinant netrin.It is proposed that netrin-3 and neogenin may promote myogenic differentiation by an autocrine mechanism as components of a higher order complex of several promyogenic cell surface proteins.

View Article: PubMed Central - PubMed

Affiliation: Brookdale Department of Molecular, Cell and Developmental Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.

ABSTRACT
Differentiation of skeletal myoblasts into multinucleated myotubes is a multistep process orchestrated by several families of transcription factors, including myogenic bHLH and NFAT proteins. The activities of these factors and formation of myotubes are regulated by signal transduction pathways, but few extracellular factors that might initiate such signals have been identified. One exception is a cell surface complex containing promyogenic Ig superfamily members (CDO and BOC) and cadherins. Netrins and their receptors are established regulators of axon guidance, but little is known of their function outside the nervous system. We report here that myoblasts express the secreted factor netrin-3 and its receptor, neogenin. These proteins stimulate myotube formation and enhance myogenic bHLH- and NFAT-dependent transcription. Furthermore, neogenin binds to CDO in a cis fashion, and myoblasts lacking CDO are defective in responding to recombinant netrin. It is proposed that netrin-3 and neogenin may promote myogenic differentiation by an autocrine mechanism as components of a higher order complex of several promyogenic cell surface proteins.

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A working model for a promyogenic cell surface complex. A complex of cell surface receptors and adhesion molecules found at sites of myoblast cell–cell contact includes CDO and BOC, which may function as a receptor for a yet-to-be identified ligand. CDO and BOC interact in cis with N- and M-cadherins, which bind β- and α-catenin. CDO and BOC also interact with neogenin, a receptor for netrin-3. Multiple signals appear to emanate from this complex, resulting in activation of myogenic bHLH and NFAT transcription factors and alteration of the actin cytoskeleton in preparation for fusion. Note that although cis dimers of cadherins are shown, no stoichiometry of complex formation between CDO, BOC and neogenin, or between these proteins and cadherins, is implied by the figure. Note also that the experiments that support this working model do not distinguish between the existence of a single complex containing each protein shown or multiple complexes in which some components may be mutually exclusive. See text for further details.
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fig9: A working model for a promyogenic cell surface complex. A complex of cell surface receptors and adhesion molecules found at sites of myoblast cell–cell contact includes CDO and BOC, which may function as a receptor for a yet-to-be identified ligand. CDO and BOC interact in cis with N- and M-cadherins, which bind β- and α-catenin. CDO and BOC also interact with neogenin, a receptor for netrin-3. Multiple signals appear to emanate from this complex, resulting in activation of myogenic bHLH and NFAT transcription factors and alteration of the actin cytoskeleton in preparation for fusion. Note that although cis dimers of cadherins are shown, no stoichiometry of complex formation between CDO, BOC and neogenin, or between these proteins and cadherins, is implied by the figure. Note also that the experiments that support this working model do not distinguish between the existence of a single complex containing each protein shown or multiple complexes in which some components may be mutually exclusive. See text for further details.

Mentions: It has long been appreciated that cell–cell contact and/or high cell density positively regulates myogenesis. This is apparent in disparate phenomena, such as the community effect in determination of the muscle lineage and the need for aggregation for differentiation of certain myogenic cell lines (Gurdon et al., 1993; Skerjanc et al., 1994; Redfield et al., 1997). We have been studying a cell surface complex found at sites of cell–cell contact which is depicted as a model in Fig. 9 and that includes: (a) the related Ig/FNIII proteins CDO and BOC; and (b) the promyogenic cell adhesion molecules, N- and M-cadherin, and the cadherin-associated proteins β- and α-catenin (Kang et al., 2002, 2003; and unpublished data for α-catenin). This complex is well-situated to coordinate multiple aspects of myogenesis. CDO signals to posttranslationally activate MyoD family members through increased heterodimerization with E proteins, most likely via CDO-directed phosphorylation of E12/E47 (Cole et al., 2004). Cadherins mediate cell–cell adhesion via tethering to the actin cytoskeleton and signal to increase the activity of the promyogenic small GTPase, RhoA (Takano et al., 1998; Charrasse et al., 2002). This work demonstrated that neogenin also binds to CDO in a cis fashion. Furthermore, netrin-3 and cadherins co-immunoprecipitated with neogenin. By analogy with netrin-1 and DCC (Stein et al., 2001), it seems likely that netrin-3 binds directly to neogenin; however, the neogenin-cadherin interaction might occur directly or indirectly via neogenin binding to CDO and/or BOC, which may provide direct association with cadherins. The formation of such a receptor complex or complexes in myoblasts resembles an emerging picture of axon guidance receptor complexes in growth cones. DCC/UNC-40 family proteins (which include neogenin) interact in cis with netrin receptors of the UNC5 family; with Robo proteins, which are Ig/FNIII domain-containing receptors for the Slit family of ligands; and with an Ig/FNIII domain-containing receptor tyrosine phosphatase (Hong et al., 1999; Stein and Tessier-Lavigne, 2001; Chang et al., 2004). Robo receptors, in turn, can form cis complexes with N-cadherin (Rhee et al., 2002).


Netrins and neogenin promote myotube formation.

Kang JS, Yi MJ, Zhang W, Feinleib JL, Cole F, Krauss RS - J. Cell Biol. (2004)

A working model for a promyogenic cell surface complex. A complex of cell surface receptors and adhesion molecules found at sites of myoblast cell–cell contact includes CDO and BOC, which may function as a receptor for a yet-to-be identified ligand. CDO and BOC interact in cis with N- and M-cadherins, which bind β- and α-catenin. CDO and BOC also interact with neogenin, a receptor for netrin-3. Multiple signals appear to emanate from this complex, resulting in activation of myogenic bHLH and NFAT transcription factors and alteration of the actin cytoskeleton in preparation for fusion. Note that although cis dimers of cadherins are shown, no stoichiometry of complex formation between CDO, BOC and neogenin, or between these proteins and cadherins, is implied by the figure. Note also that the experiments that support this working model do not distinguish between the existence of a single complex containing each protein shown or multiple complexes in which some components may be mutually exclusive. See text for further details.
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Related In: Results  -  Collection

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fig9: A working model for a promyogenic cell surface complex. A complex of cell surface receptors and adhesion molecules found at sites of myoblast cell–cell contact includes CDO and BOC, which may function as a receptor for a yet-to-be identified ligand. CDO and BOC interact in cis with N- and M-cadherins, which bind β- and α-catenin. CDO and BOC also interact with neogenin, a receptor for netrin-3. Multiple signals appear to emanate from this complex, resulting in activation of myogenic bHLH and NFAT transcription factors and alteration of the actin cytoskeleton in preparation for fusion. Note that although cis dimers of cadherins are shown, no stoichiometry of complex formation between CDO, BOC and neogenin, or between these proteins and cadherins, is implied by the figure. Note also that the experiments that support this working model do not distinguish between the existence of a single complex containing each protein shown or multiple complexes in which some components may be mutually exclusive. See text for further details.
Mentions: It has long been appreciated that cell–cell contact and/or high cell density positively regulates myogenesis. This is apparent in disparate phenomena, such as the community effect in determination of the muscle lineage and the need for aggregation for differentiation of certain myogenic cell lines (Gurdon et al., 1993; Skerjanc et al., 1994; Redfield et al., 1997). We have been studying a cell surface complex found at sites of cell–cell contact which is depicted as a model in Fig. 9 and that includes: (a) the related Ig/FNIII proteins CDO and BOC; and (b) the promyogenic cell adhesion molecules, N- and M-cadherin, and the cadherin-associated proteins β- and α-catenin (Kang et al., 2002, 2003; and unpublished data for α-catenin). This complex is well-situated to coordinate multiple aspects of myogenesis. CDO signals to posttranslationally activate MyoD family members through increased heterodimerization with E proteins, most likely via CDO-directed phosphorylation of E12/E47 (Cole et al., 2004). Cadherins mediate cell–cell adhesion via tethering to the actin cytoskeleton and signal to increase the activity of the promyogenic small GTPase, RhoA (Takano et al., 1998; Charrasse et al., 2002). This work demonstrated that neogenin also binds to CDO in a cis fashion. Furthermore, netrin-3 and cadherins co-immunoprecipitated with neogenin. By analogy with netrin-1 and DCC (Stein et al., 2001), it seems likely that netrin-3 binds directly to neogenin; however, the neogenin-cadherin interaction might occur directly or indirectly via neogenin binding to CDO and/or BOC, which may provide direct association with cadherins. The formation of such a receptor complex or complexes in myoblasts resembles an emerging picture of axon guidance receptor complexes in growth cones. DCC/UNC-40 family proteins (which include neogenin) interact in cis with netrin receptors of the UNC5 family; with Robo proteins, which are Ig/FNIII domain-containing receptors for the Slit family of ligands; and with an Ig/FNIII domain-containing receptor tyrosine phosphatase (Hong et al., 1999; Stein and Tessier-Lavigne, 2001; Chang et al., 2004). Robo receptors, in turn, can form cis complexes with N-cadherin (Rhee et al., 2002).

Bottom Line: These proteins stimulate myotube formation and enhance myogenic bHLH- and NFAT-dependent transcription.Furthermore, neogenin binds to CDO in a cis fashion, and myoblasts lacking CDO are defective in responding to recombinant netrin.It is proposed that netrin-3 and neogenin may promote myogenic differentiation by an autocrine mechanism as components of a higher order complex of several promyogenic cell surface proteins.

View Article: PubMed Central - PubMed

Affiliation: Brookdale Department of Molecular, Cell and Developmental Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.

ABSTRACT
Differentiation of skeletal myoblasts into multinucleated myotubes is a multistep process orchestrated by several families of transcription factors, including myogenic bHLH and NFAT proteins. The activities of these factors and formation of myotubes are regulated by signal transduction pathways, but few extracellular factors that might initiate such signals have been identified. One exception is a cell surface complex containing promyogenic Ig superfamily members (CDO and BOC) and cadherins. Netrins and their receptors are established regulators of axon guidance, but little is known of their function outside the nervous system. We report here that myoblasts express the secreted factor netrin-3 and its receptor, neogenin. These proteins stimulate myotube formation and enhance myogenic bHLH- and NFAT-dependent transcription. Furthermore, neogenin binds to CDO in a cis fashion, and myoblasts lacking CDO are defective in responding to recombinant netrin. It is proposed that netrin-3 and neogenin may promote myogenic differentiation by an autocrine mechanism as components of a higher order complex of several promyogenic cell surface proteins.

Show MeSH
Related in: MedlinePlus