Notch3 and Mef2c proteins are mutually antagonistic via Mkp1 protein and miR-1/206 microRNAs in differentiating myoblasts

Jeffrey Gagan, Bijan K. Dey, Ryan Layer, Zhen Yan, Anindya Dutta

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)40360-40370
Number of pages11
JournalJournal of Biological Chemistry
Volume287
Issue number48
DOIs
StatePublished - Nov 23 2012
Externally publishedYes

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Myoblasts
MicroRNAs
Satellites
p38 Mitogen-Activated Protein Kinases
Stem cells
Phosphoric Monoester Hydrolases
Muscle
Proteins
Transcription Factors
Chemical activation
Skeletal Muscle Fibers
Degradation
Muscle Cells
Skeletal Muscle
Stem Cells
Down-Regulation
Notch3 Receptor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Notch3 and Mef2c proteins are mutually antagonistic via Mkp1 protein and miR-1/206 microRNAs in differentiating myoblasts. / Gagan, Jeffrey; Dey, Bijan K.; Layer, Ryan; Yan, Zhen; Dutta, Anindya.

In: Journal of Biological Chemistry, Vol. 287, No. 48, 23.11.2012, p. 40360-40370.

Research output: Contribution to journalArticle

Gagan, Jeffrey ; Dey, Bijan K. ; Layer, Ryan ; Yan, Zhen ; Dutta, Anindya. / Notch3 and Mef2c proteins are mutually antagonistic via Mkp1 protein and miR-1/206 microRNAs in differentiating myoblasts. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 48. pp. 40360-40370.
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