Notch signaling imposes two distinct blocks in the differentiation of C2C12 myoblasts

Development. 1999 Apr;126(8):1689-702. doi: 10.1242/dev.126.8.1689.

Abstract

Notch signal transduction regulates expression of downstream genes through the activation of the DNA-binding protein Su(H)/CBF1. In Drosophila most of Notch signaling requires Su(H); however, some Notch-dependent processes occur in the absence of Su(H) suggesting that Notch signaling does not always involve activation of this factor. Using constitutively active forms of Notch lacking CBF1-interacting sequences we identified a Notch signaling pathway that inhibits myogenic differentiation of C2C12 myoblasts in the absence of CBF1 activation. Here we show that ligand-induced Notch signaling suppresses myogenesis in C2C12 myoblasts that express a dominant negative form of CBF1, providing additional evidence for CBF1-independent Notch signal transduction. Surprisingly mutant forms of Notch deficient in CBF1 activation are unable to antagonize MyoD activity, despite the fact that they inhibit myogenesis. Moreover, Notch-induced antagonism of MyoD requires CBF1 suggesting that the CBF1-dependent pathway mediates a cell-type-specific block in the myogenic program. However, Notch signaling in the absence of CBF1 activation blocks both myogenesis and osteogenesis, indicative of a general block in cellular differentiation. Taken together our data provide evidence for two distinct Notch signaling pathways that function to block differentiation at separate steps during the process of myogenesis in C2C12 myoblasts.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Calcium-Binding Proteins
  • Cell Differentiation*
  • Cell Line
  • Cell Lineage
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Drosophila Proteins
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism
  • Intercellular Signaling Peptides and Proteins
  • Jagged-1 Protein
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Muscles / cytology*
  • MyoD Protein / metabolism
  • Osteoblasts / cytology
  • Proteins / metabolism
  • Rats
  • Receptor, Notch1
  • Receptor, Notch2
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Saccharomyces cerevisiae Proteins*
  • Serrate-Jagged Proteins
  • Signal Transduction*
  • Transcription Factors*

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • CBF1 protein, S cerevisiae
  • Calcium-Binding Proteins
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Fungal Proteins
  • Intercellular Signaling Peptides and Proteins
  • Jagged-1 Protein
  • Membrane Proteins
  • MyoD Protein
  • Notch1 protein, mouse
  • Notch1 protein, rat
  • Notch2 protein, mouse
  • Notch2 protein, rat
  • Proteins
  • Receptor, Notch1
  • Receptor, Notch2
  • Receptors, Cell Surface
  • Saccharomyces cerevisiae Proteins
  • Ser protein, Drosophila
  • Serrate-Jagged Proteins
  • Transcription Factors