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CDO, a robo-related cell surface protein that mediates myogenic differentiation
J S Kang1, P J Mulieri, C Miller
1Department of Biochemistry, Mount Sinai School of Medicine, New York, New York 10029, USA.
Abstract:
CDO, a member of the Ig/fibronectin type III repeat subfamily of transmembrane proteins that includes the axon guidance receptor Robo, was identified by virtue of its down-regulation by the ras oncogene. We report here that one prominent site of cdo mRNA expression during murine embryogenesis is the early myogenic compartment (newly formed somites, dermomyotome and myotome). CDO is expressed in proliferating and differentiating C2C12 myoblasts and in myoblast lines derived by treating 10T1/2 fibroblasts with 5-azacytidine, but not in parental 10T1/2 cells. Overexpression of CDO in C2C12 cells accelerates differentiation, while expression of secreted soluble extracellular regions of CDO inhibits this process. Oncogenic Ras is known to block differentiation of C2C12 cells via downregulation of MyoD. Reexpression of CDO in C2C12/Ras cells induces MyoD; conversely, MyoD induces CDO. Reexpression of either CDO or MyoD rescues differentiation of C2C12/Ras cells without altering anchorage-independent growth or morphological transformation. CDO and MyoD are therefore involved in a positive feedback loop that is central to the inverse relationship between cell differentiation and transformation. It is proposed that CDO mediates, at least in part, the effects of cell-cell interactions between muscle precursors that are critical in myogenesis.
Insights
CDO (cell adhesion molecule) promotes muscle differentiation by interacting with MyoD, a key regulator. This interaction forms a positive feedback loop, counteracting Ras oncogene-induced blockage of differentiation.
Area of Science:
- Cell Biology
- Developmental Biology
- Molecular Oncology
Background:
- CDO (cell adhesion molecule) is a transmembrane protein involved in cell interactions.
- Ras oncogenes are known to inhibit cell differentiation, a process crucial for development and tissue homeostasis.
- MyoD is a master regulatory transcription factor essential for muscle cell differentiation.
Purpose of the Study:
- To investigate the role of CDO in muscle cell differentiation.
- To elucidate the relationship between CDO, Ras oncogenes, and MyoD in the context of cell differentiation and transformation.
- To explore CDO's potential role in mediating cell-cell interactions during myogenesis.
Main Methods:
- Analysis of CDO mRNA expression during murine embryogenesis.
- Overexpression and inhibition studies of CDO in C2C12 myoblasts and related cell lines.
- Investigating the interplay between CDO, Ras, and MyoD using re-expression experiments in C2C12/Ras cells.
Main Results:
- CDO is prominently expressed in the myogenic compartment during embryogenesis.
- Overexpression of CDO accelerates C2C12 myoblast differentiation, while its soluble extracellular domain inhibits it.
- CDO and MyoD expression mutually induce each other, forming a positive feedback loop that rescues differentiation in Ras-transformed cells.
Conclusions:
- CDO plays a critical role in promoting muscle cell differentiation.
- A positive feedback loop between CDO and MyoD is central to the inverse relationship between differentiation and transformation.
- CDO likely mediates cell-cell interactions crucial for myogenesis.