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Cell Aggregation Assays to Evaluate the Binding of the Drosophila Notch with Trans-Ligands and its Inhibition by Cis-Ligands
Published on: January 2, 2018
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A non-canonical Notch complex regulates adherens junctions and vascular barrier function.
William J Polacheck1,2, Matthew L Kutys1,2, Jinling Yang1,2
1The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA.
Nature
|November 22, 2017
Summary
Shear stress activates NOTCH1, a receptor crucial for vascular barrier integrity. This non-canonical pathway, independent of transcription, uses NOTCH1’s transmembrane domain to assemble adherens junctions and maintain blood vessel function.
Area of Science:
- Vascular biology
- Cell signaling
- Biophysics
Background:
- The endothelium forms a vital vascular barrier regulating transport and inflammation.
- Hemodynamic shear stress is critical for endothelial barrier function, but the underlying mechanisms are unclear.
Purpose of the Study:
- To elucidate the mechanism by which shear stress maintains endothelial barrier function.
- To investigate the role of NOTCH1 in regulating vascular barrier integrity.
Main Methods:
- Utilized an engineered organotypic model of perfused microvessels.
- Employed mouse models to validate findings.
- Investigated NOTCH1 activation and its downstream effects on adherens junctions.
Main Results:
- Shear stress triggers DLL4-dependent activation of NOTCH1, exposing its transmembrane domain.
- The NOTCH1 transmembrane domain is sufficient to restore endothelial barrier function.
- This domain facilitates a receptor complex (VE-cadherin, LAR, TRIO) that activates RAC1, driving adherens junction assembly.
Conclusions:
- A non-canonical, transcription-independent signaling pathway of NOTCH1 regulates vascular barrier function.
- This pathway links transcriptional programs with cytoskeletal remodeling via adherens junction assembly.
- NOTCH1 plays a dual role in vascular biology, encompassing both canonical transcriptional and non-canonical signaling.
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