NOV/CCN3 impairs muscle cell commitment and differentiation.
NOV (nephroblastoma overexpressed) is a member of a family of proteins which encodes secreted matrix-associated proteins. NOV is expressed during development in dermomyotome and limb buds, but its functions are still poorly defined. In order to understand the role of NOV in myogenic differentiation, C2C12 cells overexpressing NOV (C2-NOV) were generated. These cells failed to engage into myogenic differentiation, whereas they retained the ability to differentiate into osteoblasts. In differentiating conditions, C2-NOV cells remained proliferative, failed to express differentiation markers and lost their ability to form myotubes. Inhibition of differentiation by NOV was also observed with human primary muscle cells. Further examination of C2-NOV cells revealed a strong downregulation of the myogenic determination genes MyoD and Myf5 and of IGF-II expression. MyoD forced expression in C2-NOV was sufficient to restore differentiation and IGF-II induction whereas 10(-6) M insulin treatment had no effects. NOV therefore acts upstream of MyoD and does not affect IGF-II induction and signaling. HES1, a target of Notch, previously proposed to mediate NOV action, was not implicated in the inhibition of differentiation. We propose that NOV is a specific cell fate regulator in the myogenic lineage, acting negatively on key myogenic genes thus controlling the transition from progenitor cells to myoblasts.
Calhabeu
Frederico
F
Unité INSERM 515, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75371 Paris, France; Pierre and Marie Curie University, Paris.
Lafont
Jérome
J
Le Dreau
Gwenvael
G
Laurent
Maryvonne
M
Kazazian
Chantal
C
Schaeffer
Laurent
L
Martinerie
Cécile
C
Dubois
Catherine
C
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D003470:Culture Media / Q000737:chemistry; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009024:Morphogenesis; D032342:Muscle Cells / Q000166:cytology / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000196:embryology*; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D051787:Myogenic Regulatory Factor 5 / Q000235:genetics / Q000378:metabolism; D055514:Nephroblastoma Overexpressed Protein; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D055513:Connective Tissue Growth Factor; D003470:Culture Media; D018398:Homeodomain Proteins; D017874:Immediate-Early Proteins; D007328:Insulin; D007335:Insulin-Like Growth Factor II; D036341:Intercellular Signaling Peptides and Proteins; D017570:MyoD Protein; D051787:Myogenic Regulatory Factor 5; D055514:Nephroblastoma Overexpressed Protein; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; C526319:CCN3 protein, human; C526320:Ccn3 protein, mouse; C489734:Hes1 protein, mouse