Mi-2/NuRD complex protects stem cell progeny from mitogenic Notch signaling
Evanthia Zacharioudaki1, Julia Falo Sanjuan1, Sarah Bray1
1Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Knigdom.
Elife
|January 30, 2019
Summary
Stem cell differentiation requires silencing of maintenance genes. The Mi-2/NuRD complex is crucial for this process in Drosophila neural stem cells, preventing tumor-like hyperplasia.
Area of Science:
- Developmental Biology
- Cell Biology
- Genetics
Background:
- Stem cell differentiation involves downregulating stem-cell maintenance genes.
- Failures in this process can lead to tumorigenesis, such as hyperplasia in Drosophila neural stem cells (NSCs) due to excessive Notch signaling.
- Mechanisms resisting immediate hyperplasia despite excess Notch signaling suggest compensatory pathways exist.
Purpose of the Study:
- To investigate the mechanisms that normally attenuate Notch signaling and prevent immediate hyperplasia in Drosophila NSC lineages.
- To identify factors responsible for the delayed onset of hyperplasia in response to sustained Notch activity.
Main Methods:
- Live monitoring of a Notch target gene, E(spl)mγ, expression in Drosophila NSC lineages.
- Genetic screening to identify factors involved in regulating stem cell gene expression.
- Depletion of the Mi-2/NuRD ATP remodeling complex to assess its role.
Main Results:
- Normal attenuation of E(spl)mγ expression was observed even with excess Notch activity, delaying NSC property re-emergence.
- Depletion of the Mi-2/NuRD complex significantly enhanced Notch-induced hyperplasia.
- In Mi-2 depleted cells, E(spl)mγ was not extinguished in NSC progeny, indicating a failure in gene silencing.
Conclusions:
- The Mi-2/NuRD complex is essential for decommissioning stem-cell enhancers in progeny cells.
- Mi-2 facilitates the transition to differentiated fates and insensitivity to mitogenic signals like Notch.
- Dysfunction of Mi-2 can disrupt normal stem cell regulation, contributing to hyperplasia and potentially tumorigenesis.
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