Positive Regulation of Myogenic bHLH Factors and Skeletal Muscle Development by the Cell Surface Receptor CDO

Cole, Francesca; Zhang, Wei; Geyra, A.; Kang, Jong Sun; Krauss, Robert M.

doi:10.1016/j.devcel.2004.10.009

Cited by 90 publications

(112 citation statements)

References 49 publications

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“…As was observed with E15.5 limbs, neogenin protein levels were Figure 5G). Levels of MyoD and Cdo, both of which are expressed in proliferating and differentiating myoblasts (Kang et al, 1998;Sabourin et al, 1999;Cole et al, 2004), were similar in wild-type and Neo1 Gt/Gt cells. However, as seen with developing Neo1 Gt/Gt muscle masses in vivo, Neo1 Gt/Gt cells had lower levels of both myogenin and MHC compared with Neo1 ϩ/ϩ cells.…”

Section: Defective Differentiation Of Neo1 Gt/gt Myoblasts In Vitromentioning

confidence: 84%

Neogenin Regulates Skeletal Myofiber Size and Focal Adhesion Kinase and Extracellular Signal-regulated Kinase Activities In Vivo and In Vitro

Bae

Yang

Jiang

et al. 2009

MBoC

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A variety of signaling pathways participate in the development of skeletal muscle, but the extracellular cues that regulate such pathways in myofiber formation are not well understood. Neogenin is a receptor for ligands of the netrin and repulsive guidance molecule (RGM) families involved in axon guidance. We reported previously that neogenin promoted myotube formation by C2C12 myoblasts in vitro and that the related protein Cdo (also Cdon) was a potential neogenin coreceptor in myoblasts. We report here that mice homozygous for a gene-trap mutation in the Neo1 locus (encoding neogenin) develop myotomes normally but have small myofibers at embryonic day 18.5 and at 3 wk of age. Similarly, cultured myoblasts derived from such animals form smaller myotubes with fewer nuclei than myoblasts from control animals. These in vivo and in vitro defects are associated with low levels of the activated forms of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK), both known to be involved in myotube formation, and inefficient expression of certain muscle-specific proteins. Recombinant netrin-2 activates FAK and ERK in cultured myoblasts in a neogenin-and Cdo-dependent manner, whereas recombinant RGMc displays lesser ability to activate these kinases. Together, netrin-neogenin signaling is an important extracellular cue in regulation of myogenic differentiation and myofiber size. INTRODUCTIONSkeletal muscle is the most abundant tissue, by mass, in the vertebrate body. Muscles of the trunk and limbs arise from the somites, with myogenic progenitor cells derived from the dorsal region of the maturing somite, the dermomyotome (Tajbakhsh and Buckingham, 2000;Pownall et al., 2002;Charge and Rudnicki, 2004). In response to signals from the adjacent notochord, neural tube, and surface ectoderm, some dermomyotomal progenitors become committed to the muscle lineage and form the myotome, a set of differentiated muscle cells that underlies the dermomyotome. Subsequent embryonic, fetal, and postnatal stages of myogenesis are thought to involve additional muscle progenitors that migrate from the dermomyotome and ultimately establish the trunk and limb musculature, as well as satellite cells, adult muscle precursor cells (Gros et al., 2005;Kassar-Duchossoy et al., 2005;Relaix et al., 2005). Somitic progenitor cells are specified to become muscle lineage-committed myoblasts through the action of the myogenic basic helix-loop-helix transcription factors Myf5, MRF4, and MyoD, whereas differentiation of myoblasts is regulated by myogenin, MyoD, and MRF4 (Tajbakhsh, 2005). These and other transcription factors coordinate the process of differentiation, including cell cycle withdrawal, expression of muscle-specific proteins, cellular elongation, and fusion into multinucleated myofibers. Although transcriptional regulation is at the core of myogenesis, the formation and growth of myofibers is also controlled by a variety of signaling ligands and their receptors, including insulin-like growth factor-1, fibroblast growth fac...

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Section: Defective Differentiation Of Neo1 Gt/gt Myoblasts In Vitromentioning

confidence: 84%

Neogenin Regulates Skeletal Myofiber Size and Focal Adhesion Kinase and Extracellular Signal-regulated Kinase Activities In Vivo and In Vitro

Bae

Yang

Jiang

et al. 2009

MBoC

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“…C2C12, NIH 3T3, and 293T cells were cultured as previously described (12,39). Myoblasts derived from hindlimbs of Cdo +/+ and Cdo −/− mice were obtained by the method of Rando and Blau (40) and cultured as described (7,8). 293T cells were transfected with Ncad-Fc expression vector (a gift of R. M. Mege) and FuGene6 (Roche) and 36 h later, cultures were passaged into medium containing 0.5 mg/mL hygromycin (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

“…Multiprotein complexes that contain the promyogenic cell surface receptor Cdo play a significant (although not exclusive) role in p38 activation during myogenesis (5-7). Cdo −/− mice and myoblasts display delayed skeletal muscle development and defective differentiation in vitro, respectively (7,8). Similarly, RNAi-mediated depletion of Cdo from C2C12 myoblasts causes them to differentiate inefficiently (5, 7).…”

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confidence: 99%

N-cadherin ligation, but not Sonic hedgehog binding, initiates Cdo-dependent p38α/β MAPK signaling in skeletal myoblasts

Lü

Krauss

2010

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

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The p38α/β mitogen-activated protein kinase (MAPK) pathway promotes muscle-specific gene expression and myoblast differentiation but how pathway activity is initiated during these processes is poorly understood. During myoblast differentiation, the intracellular region of the promyogenic cell surface protein Cdo (also known as Cdon) binds to Bnip-2 and JLP, scaffold proteins for Cdc42 and p38α/β MAPK, respectively. The Bnip-2/Cdc42 and JLP/p38α/β complexes associate in a Cdo-dependent manner, resulting in Bnip-2/Cdc42-dependent p38α/β activation and stimulation of cell differentiation. Although the Cdo ectodomain binds to several different proteins, it is unclear how Cdo-dependent p38α/β activation is initiated. In myoblasts, Cdo interacts with the cell–cell adhesion molecule N-cadherin. Cdo also binds directly to the secreted morphogen Sonic hedgehog (Shh) to promote Shh pathway signaling. We report here that N-cadherin ligation activates p38α/β in myoblasts in a Cdo-, Bnip-2-, and JLP-dependent manner. Furthermore, these proteins and activated Cdc42 cluster at sites of N-cadherin ligation. In contrast, neither JLP nor Bnip-2 is associated with Cdo bound to Shh, and Shh does not activate p38α/β in myoblasts. Taken together, these results link cadherin-based cell–cell adhesion to a defined signaling pathway (Cdo → p38α/β) that directly regulates a cell-type-specific differentiation program. Furthermore, they are consistent with a model whereby Cdo serves as a multifunctional coreceptor with mechanistically distinct roles in multiple signaling pathways.

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“…Cdon +/− mice were maintained as previously described (25,27). Briefly, Cdon +/− mice were kept on a C57BL/6 background and 2-or 3-moold mice were used for breeding.…”

Section: Methodsmentioning

confidence: 99%

“…These data suggest that Cdon is required for the control of Wnt signaling to prevent cardiac remodeling. (25)(26)(27)(28)(29). Recently, we have shown that Cdon negatively regulates Wnt signaling to promote neuronal differentiation and ventral cell fate determination in forebrain development (28).…”

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confidence: 99%

Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling

Jeong

Kim

Pyun

et al. 2017

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

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On pathological stress, Wnt signaling is reactivated and induces genes associated with cardiac remodeling and fibrosis. We have previously shown that a cell surface receptor Cdon (cell-adhesion associated, oncogene regulated) suppresses Wnt signaling to promote neuronal differentiation however its role in heart is unknown. Here, we demonstrate a critical role of Cdon in cardiac function and remodeling. Cdon is expressed and predominantly localized at intercalated disk in both mouse and human hearts. Cdon-deficient mice develop cardiac dysfunction including reduced ejection fraction and ECG abnormalities.Cdon−/−hearts exhibit increased fibrosis and up-regulation of genes associated with cardiac remodeling and fibrosis. Electrical remodeling was demonstrated by up-regulation and mislocalization of the gap junction protein, Connexin 43 (Cx43) inCdon−/−hearts. In agreement with altered Cx43 expression, functional analysis both usingCdon−/−cardiomyocytes and shRNA-mediated knockdown in rat cardiomyocytes shows aberrant gap junction activities. Analysis of the underlying mechanism reveals thatCdon−/−hearts exhibit hyperactive Wnt signaling as evident by β-catenin accumulation and Axin2 up-regulation. On the other hand, the treatment of rat cardiomyocytes with a Wnt activator TWS119 reduces Cdon levels and aberrant Cx43 activities, similarly to Cdon-deficient cardiomyocytes, suggesting a negative feedback between Cdon and Wnt signaling. Finally, inhibition of Wnt/β-catenin signaling by XAV939, IWP2 or dickkopf (DKK)1 prevented Cdon depletion-induced up-regulation of collagen 1a and Cx43. Taken together, these results demonstrate that Cdon deficiency causes hyperactive Wnt signaling leading to aberrant intercellular coupling and cardiac fibrosis. Cdon exhibits great potential as a target for the treatment of cardiac fibrosis and cardiomyopathy.

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Positive Regulation of Myogenic bHLH Factors and Skeletal Muscle Development by the Cell Surface Receptor CDO

Cited by 90 publications

References 49 publications

Neogenin Regulates Skeletal Myofiber Size and Focal Adhesion Kinase and Extracellular Signal-regulated Kinase Activities In Vivo and In Vitro

Neogenin Regulates Skeletal Myofiber Size and Focal Adhesion Kinase and Extracellular Signal-regulated Kinase Activities In Vivo and In Vitro

N-cadherin ligation, but not Sonic hedgehog binding, initiates Cdo-dependent p38α/β MAPK signaling in skeletal myoblasts

Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling

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