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Updated: Dec 20, 2025
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Retroviral Infection of Murine Embryonic Stem Cell Derived Embryoid Body Cells for Analysis of Hematopoietic Differentiation
Published on: October 20, 2014
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Yap1-Scribble polarization is required for hematopoietic stem cell division and fate
Mark J Althoff1,2,3, Ramesh C Nayak1,2, Shailaja Hegde1,2
1Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Blood
|June 3, 2020
Summary
Hematopoietic stem cell (HSC) stress response relies on Yap1 and Taz. Their interaction with Scribble controls cell division and fate, impacting HSC regeneration and stress vulnerability.
Area of Science:
- Cell Biology
- Stem Cell Biology
- Signaling Pathways
Background:
- The Hippo signaling pathway, including Yap1 and Taz, is crucial for tissue growth.
- Hematopoietic stem cell (HSC) function and stress response mechanisms are not fully understood.
- The role of protein-scaffolding interactions in regulating HSC fate is an active area of research.
Purpose of the Study:
- To investigate the role of Yap1 and Taz in HSC fitness and stress response.
- To elucidate the mechanism by which Yap1 and Scribble regulate HSC fate determination.
- To explore the interplay between Hippo signaling, Scribble, and small GTPases in HSC biology.
Main Methods:
- Gene deletion studies (Yap1, Taz, Scribble) in HSCs.
- Analysis of HSC quiescence, self-renewal, and stress resistance (e.g., 5-fluorouracil treatment).
- Immunofluorescence microscopy to assess protein localization (Yap1, Scribble, Cdc42).
- Assays to measure cytoplasmic Cdc42 activity and Rac activation.
- Competitive reconstitution assays to evaluate HSC function in vivo.
Main Results:
- Deletion of Yap1 and Taz impairs HSC quiescence, symmetric self-renewal, and increases sensitivity to chemotherapy.
- Yap1's cytosolic localization, mediated by Scribble, is critical for regulating HSC fate.
- Scribble and Yap1 coordinate to control cytoplasmic Cdc42 activity, influencing HSC asymmetric division.
- Loss of Scribble disrupts Yap1-Cdc42 copolarization, leading to increased self-renewing HSCs with enhanced reconstitution potential.
- Combined deletion of Scribble, Yap1, and Taz upregulates Rac-specific guanine nucleotide exchange factors, activating Rac and restoring HSC fitness.
Conclusions:
- Scribble acts as a crucial link between Cdc42 and the Hippo signaling pathway in HSCs.
- Yap1 and Scribble interaction is essential for regulating Cdc42-dependent asymmetric cell division and HSC fate.
- The Scribble/Yap1/Cdc42 axis is a key determinant of HSC response to stress and maintains stem cell pool homeostasis.
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