Document Detail

The role of Delta-like 1 shedding in muscle cell self-renewal and differentiation.
MedLine Citation:
PMID:  18957511     Owner:  NLM     Status:  MEDLINE    
Myogenic cells have the ability to adopt two divergent fates upon exit from the cell cycle: differentiation or self-renewal. The Notch signaling pathway is a well-known negative regulator of myogenic differentiation. Using mouse primary myoblasts cultured in vitro or C2C12 myogenic cells, we found that Notch activity is essential for maintaining the expression of Pax7, a transcription factor associated with the self-renewal lineage, in quiescent undifferentiated myoblasts after they exit the cell cycle. Stimulation of the Notch pathway by expression of a constitutively active Notch-1, or co-culture of myogenic cells with CHO cells transfected with Delta like-1 (DLL1), increases the level of Pax7. DLL1, a ligand for Notch receptor, is shed by ADAM metalloproteases in a pool of Pax7+ C2C12 reserve cells, but it remains intact in differentiated myotubes. DLL1 shedding changes the receptor/ligand ratio and modulates the level of Notch signaling. Inhibition of DLL1 cleavage by a soluble, dominant-negative mutant form of ADAM12 leads to elevation of Notch signaling, inhibition of differentiation, and expansion of the pool of self-renewing Pax7+/MyoD- cells. These results suggest that ADAM-mediated shedding of DLL1 in a subset of cells during myogenic differentiation in vitro contributes to downregulation of Notch signaling in neighboring cells and facilitates their progression into differentiation. We propose that the proteolytic processing of DLL1 helps achieve an asymmetry in Notch signaling in initially equivalent myogenic cells and helps sustain the balance between differentiation and self-renewal.
Danqiong Sun; Hui Li; Anna Zolkiewska
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-10-28
Journal Detail:
Title:  Journal of cell science     Volume:  121     ISSN:  0021-9533     ISO Abbreviation:  J. Cell. Sci.     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-11-06     Completed Date:  2009-06-04     Revised Date:  2014-09-16    
Medline Journal Info:
Nlm Unique ID:  0052457     Medline TA:  J Cell Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  3815-23     Citation Subset:  IM    
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MeSH Terms
Cell Differentiation*
Cell Line
Cells, Cultured
Intercellular Signaling Peptides and Proteins / genetics,  metabolism*
Mice, Inbred C57BL
Myoblasts / cytology*,  metabolism
Myocytes, Smooth Muscle / cytology*,  metabolism
PAX7 Transcription Factor / genetics,  metabolism
Signal Transduction
Grant Support
GM065528/GM/NIGMS NIH HHS; R01 GM065528/GM/NIGMS NIH HHS; R01 GM065528-01A2/GM/NIGMS NIH HHS; R01 GM065528-02/GM/NIGMS NIH HHS; R01 GM065528-03/GM/NIGMS NIH HHS; R01 GM065528-04/GM/NIGMS NIH HHS
Reg. No./Substance:
0/Dlk1 protein, mouse; 0/Intercellular Signaling Peptides and Proteins; 0/PAX7 Transcription Factor; 0/Pax7 protein, mouse

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