Mi-2/NuRD complex protects stem cell progeny from mitogenic Notch signaling.


Type
Article
Change log
Authors
Zacharioudaki, Evanthia 
Falo Sanjuan, Julia  ORCID logo  https://orcid.org/0000-0002-3563-4789
Abstract

To progress towards differentiation, progeny of stem cells need to extinguish expression of stem-cell maintenance genes. Failures in such mechanisms can drive tumorigenesis. In Drosophila neural stem cell (NSC) lineages, excessive Notch signalling results in supernumerary NSCs causing hyperplasia. However, onset of hyperplasia is considerably delayed implying there are mechanisms that resist the mitogenic signal. Monitoring the live expression of a Notch target gene, E(spl)mγ, revealed that normal attenuation is still initiated in the presence of excess Notch activity so that re-emergence of NSC properties occurs only in older progeny. Screening for factors responsible, we found that depletion of Mi-2/NuRD ATP remodeling complex dramatically enhanced Notch-induced hyperplasia. Under these conditions, E(spl)mγ was no longer extinguished in NSC progeny. We propose that Mi-2 is required for decommissioning stem-cell enhancers in their progeny, enabling the switch towards more differentiated fates and rendering them insensitive to mitogenic factors such as Notch.

Description
Keywords
D. melanogaster, Notch, NuRD Complex, chromosomes, developmental biology, gene expression, stem cells, Adenosine Triphosphatases, Animals, Autoantigens, Basic Helix-Loop-Helix Transcription Factors, Carcinogenesis, Cell Differentiation, Cell Lineage, Cell Proliferation, Drosophila Proteins, Drosophila melanogaster, Gene Expression Regulation, Developmental, Humans, Hyperplasia, Models, Biological, Neural Stem Cells, Neurons, Protein Binding, Receptors, Notch, Repressor Proteins, Signal Transduction
Journal Title
Elife
Conference Name
Journal ISSN
2050-084X
2050-084X
Volume Title
8
Publisher
eLife Sciences Publications, Ltd
Sponsorship
Medical Research Council (MR/L007177/1)
Wellcome Trust (109144/Z/15/Z)