Related Experiment Videos
Notch signaling inhibits muscle cell differentiation through a CBF1-independent pathway
C Shawber1, D Nofziger, J J Hsieh
1Department of Biological Chemistry, UCLA School of Medicine, Los Angeles, CA 90095-1737, USA.
Abstract:
Notch controls cell fate by inhibiting cellular differentiation, presumably through activation of the transcriptional regulator human C promoter Binding Factor (CBF1), which transactivates the hairy and Enhancer of split (HES-1) gene. However, we describe constitutively active forms of Notch1, which inhibit muscle cell differentiation but do not interact with CBF1 or upregulate endogenous HES-1 expression. In addition, Jagged-Notch interactions that prevent the expression of muscle cell specific genes do not involve the upregulation of endogenous HES-1. In fact, exogenous expression of HES-1 in C2C12 myoblasts does not block myogenesis. Our data demonstrate the existence of a CBF1-independent pathway by which Notch inhibits differentiation. We therefore propose that Notch signaling activates at least two different pathways: one which involves CBF1 as an intermediate and one which does not.
Insights
Notch signaling inhibits cell differentiation through at least two pathways. One pathway involves human C promoter Binding Factor (CBF1), while a second, novel pathway functions independently of CBF1.
Area of Science:
- Cell biology
- Developmental biology
- Molecular signaling
Background:
- Notch signaling is crucial for controlling cell fate and differentiation.
- It is widely believed that Notch exerts its inhibitory effects on differentiation via the transcriptional regulator human C promoter Binding Factor (CBF1) and the HES-1 gene.
Purpose of the Study:
- To investigate the precise mechanisms by which Notch signaling inhibits muscle cell differentiation.
- To determine if CBF1 and HES-1 are essential components of all Notch-mediated differentiation inhibition.
Main Methods:
- Utilized constitutively active forms of Notch1.
- Examined Jagged-Notch interactions.
- Assessed the impact of exogenous HES-1 expression in C2C12 myoblasts.
Main Results:
- Constitutively active Notch1 inhibited muscle differentiation independently of CBF1 interaction or HES-1 upregulation.
- Jagged-Notch interactions did not upregulate HES-1 but still prevented muscle-specific gene expression.
- Exogenous HES-1 expression did not inhibit myogenesis in C2C12 myoblasts.
Conclusions:
- Notch signaling employs at least two distinct pathways to inhibit cellular differentiation.
- One pathway is CBF1-dependent, while a second, previously undescribed pathway is CBF1-independent.