Notch3 and Mef2c proteins are mutually antagonistic via Mkp1 protein and miR-1/206 microRNAs in differentiating myoblasts.
BACKGROUND
Notch3 is expressed in myogenic precursors, but its function is not well known.


RESULTS
Notch3 represses the activity of Mef2c and is in turn inhibited by the microRNAs-1 and -206.


CONCLUSIONS
Notch3 serves as a regulator for preventing premature myogenic differentiation.


CONCLUSIONS
Understanding how precocious differentiation is prevented is critical for designing therapy for skeletal muscle regeneration. The Notch signaling pathway is a well known regulator of skeletal muscle stem cells known as satellite cells. Loss of Notch1 signaling leads to spontaneous myogenic differentiation. Notch1, normally expressed in satellite cells, is targeted for proteasomal degradation by Numb during differentiation. A homolog of Notch1, Notch3, is also expressed in these cells but is not inhibited by Numb. We find that Notch3 is paradoxically up-regulated during the early stages of differentiation by an enhancer that requires both MyoD and activated Notch1. Notch3 itself strongly inhibits the myogenic transcription factor Mef2c, most likely by increasing the p38 phosphatase Mkp1, which inhibits the Mef2c activator p38 MAP kinase. Active Notch3 decreases differentiation. Mef2c, however, induces microRNAs miR-1 and miR-206, which directly down-regulate Notch3 and allow differentiation to proceed. Thus, the myogenic differentiation-induced microRNAs miR-1 and -206 are important for differentiation at least partly because they turn off Notch3. We suggest that the transient expression of Notch3 early in differentiation generates a temporal lag between myoblast activation by MyoD and terminal differentiation into myotubes directed by Mef2c.
Department of Biochemistry and Molecular Genetics, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Jeffrey
J
Gagan
Bijan K
BK
Dey
Ryan
R
Layer
Zhen
Z
Yan
Anindya
A
Dutta
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D015536:Down-Regulation; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; C540669:Mirn206 microRNA, mouse; D017570:MyoD Protein; D018006:Myogenic Regulatory Factors; C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse