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Real-time Bioluminescence Imaging of Notch Signaling Dynamics during Murine Neurogenesis
Published on: December 12, 2019
Fbw7 repression by hes5 creates a feedback loop that modulates Notch-mediated intestinal and neural stem cell fate
Rocio Sancho1, Sophia M Blake, Christian Tendeng
1Mammalian Genetics Laboratory, CR UK London Research Institute, Lincoln's Inn Fields Laboratories, London, United Kingdom.
Plos Biology
|June 19, 2013
Summary
The F-box and WD repeat domain-containing protein 7 (FBW7) E3 ligase is vital for cell differentiation. Notch signaling, via HES5, represses FBW7β transcription, a mechanism essential for cell fate decisions.
Area of Science:
- Cell Biology
- Developmental Biology
- Molecular Oncology
Background:
- FBW7 is an SCF-type E3 ubiquitin ligase targeting key proteins in development and cancer.
- Notch signaling is critical for cell differentiation, particularly lateral inhibition.
- FBW7 targets include Notch proteins, suggesting a regulatory link.
Purpose of the Study:
- To investigate the regulatory relationship between Notch signaling and FBW7 isoforms.
- To elucidate the role of HES5 in controlling FBW7β transcription.
- To understand the implications for stem cell differentiation and lateral inhibition.
Main Methods:
- Analysis of Fbw7 isoform regulation by Notch signaling components.
- In vivo studies using Fbw7 heterozygous mice.
- Genetic rescue experiments with Hes5 inactivation.
- In silico modeling of regulatory feedback loops.
Main Results:
- HES5 directly represses transcription of the Fbw7β isoform.
- Fbw7 haploinsufficiency impairs intestinal and neural stem cell differentiation.
- Inactivation of Hes5 rescues these differentiation defects.
- A positive feedback loop involving NICD/HES5/FBW7β explains Fbw7 haploinsufficiency.
Conclusions:
- Notch signaling, through HES5, represses Fbw7β transcription, coupling cell fate specification to lateral inhibition.
- This regulatory axis is essential for proper stem cell differentiation.
- Dysregulation of this loop contributes to developmental defects observed in Fbw7 haploinsufficiency.
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