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A new model of Notch signalling: Control of Notch receptor cis-inhibition via Notch ligand dimers

All tissue development and replenishment relies upon the breaking of symmetries leading to the morphological and operational differentiation of progenitor cells into more specialized cells. One of the main engines driving this process is the Notch signal transduction pathway, a ubiquitous signalling...

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Autores principales: Chen, Daipeng, Forghany, Zary, Liu, Xinxin, Wang, Haijiang, Merks, Roeland M. H., Baker, David A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9891537/
https://www.ncbi.nlm.nih.gov/pubmed/36668673
http://dx.doi.org/10.1371/journal.pcbi.1010169
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author Chen, Daipeng
Forghany, Zary
Liu, Xinxin
Wang, Haijiang
Merks, Roeland M. H.
Baker, David A.
author_facet Chen, Daipeng
Forghany, Zary
Liu, Xinxin
Wang, Haijiang
Merks, Roeland M. H.
Baker, David A.
author_sort Chen, Daipeng
collection PubMed
description All tissue development and replenishment relies upon the breaking of symmetries leading to the morphological and operational differentiation of progenitor cells into more specialized cells. One of the main engines driving this process is the Notch signal transduction pathway, a ubiquitous signalling system found in the vast majority of metazoan cell types characterized to date. Broadly speaking, Notch receptor activity is governed by a balance between two processes: 1) intercellular Notch transactivation triggered via interactions between receptors and ligands expressed in neighbouring cells; 2) intracellular cis inhibition caused by ligands binding to receptors within the same cell. Additionally, recent reports have also unveiled evidence of cis activation. Whilst context-dependent Notch receptor clustering has been hypothesized, to date, Notch signalling has been assumed to involve an interplay between receptor and ligand monomers. In this study, we demonstrate biochemically, through a mutational analysis of DLL4, both in vitro and in tissue culture cells, that Notch ligands can efficiently self-associate. We found that the membrane proximal EGF-like repeat of DLL4 was necessary and sufficient to promote oligomerization/dimerization. Mechanistically, our experimental evidence supports the view that DLL4 ligand dimerization is specifically required for cis-inhibition of Notch receptor activity. To further substantiate these findings, we have adapted and extended existing ordinary differential equation-based models of Notch signalling to take account of the ligand dimerization-dependent cis-inhibition reported here. Our new model faithfully recapitulates our experimental data and improves predictions based upon published data. Collectively, our work favours a model in which net output following Notch receptor/ligand binding results from ligand monomer-driven Notch receptor transactivation (and cis activation) counterposed by ligand dimer-mediated cis-inhibition.
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spelling pubmed-98915372023-02-02 A new model of Notch signalling: Control of Notch receptor cis-inhibition via Notch ligand dimers Chen, Daipeng Forghany, Zary Liu, Xinxin Wang, Haijiang Merks, Roeland M. H. Baker, David A. PLoS Comput Biol Research Article All tissue development and replenishment relies upon the breaking of symmetries leading to the morphological and operational differentiation of progenitor cells into more specialized cells. One of the main engines driving this process is the Notch signal transduction pathway, a ubiquitous signalling system found in the vast majority of metazoan cell types characterized to date. Broadly speaking, Notch receptor activity is governed by a balance between two processes: 1) intercellular Notch transactivation triggered via interactions between receptors and ligands expressed in neighbouring cells; 2) intracellular cis inhibition caused by ligands binding to receptors within the same cell. Additionally, recent reports have also unveiled evidence of cis activation. Whilst context-dependent Notch receptor clustering has been hypothesized, to date, Notch signalling has been assumed to involve an interplay between receptor and ligand monomers. In this study, we demonstrate biochemically, through a mutational analysis of DLL4, both in vitro and in tissue culture cells, that Notch ligands can efficiently self-associate. We found that the membrane proximal EGF-like repeat of DLL4 was necessary and sufficient to promote oligomerization/dimerization. Mechanistically, our experimental evidence supports the view that DLL4 ligand dimerization is specifically required for cis-inhibition of Notch receptor activity. To further substantiate these findings, we have adapted and extended existing ordinary differential equation-based models of Notch signalling to take account of the ligand dimerization-dependent cis-inhibition reported here. Our new model faithfully recapitulates our experimental data and improves predictions based upon published data. Collectively, our work favours a model in which net output following Notch receptor/ligand binding results from ligand monomer-driven Notch receptor transactivation (and cis activation) counterposed by ligand dimer-mediated cis-inhibition. Public Library of Science 2023-01-20 /pmc/articles/PMC9891537/ /pubmed/36668673 http://dx.doi.org/10.1371/journal.pcbi.1010169 Text en © 2023 Chen et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Chen, Daipeng
Forghany, Zary
Liu, Xinxin
Wang, Haijiang
Merks, Roeland M. H.
Baker, David A.
A new model of Notch signalling: Control of Notch receptor cis-inhibition via Notch ligand dimers
title A new model of Notch signalling: Control of Notch receptor cis-inhibition via Notch ligand dimers
title_full A new model of Notch signalling: Control of Notch receptor cis-inhibition via Notch ligand dimers
title_fullStr A new model of Notch signalling: Control of Notch receptor cis-inhibition via Notch ligand dimers
title_full_unstemmed A new model of Notch signalling: Control of Notch receptor cis-inhibition via Notch ligand dimers
title_short A new model of Notch signalling: Control of Notch receptor cis-inhibition via Notch ligand dimers
title_sort new model of notch signalling: control of notch receptor cis-inhibition via notch ligand dimers
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9891537/
https://www.ncbi.nlm.nih.gov/pubmed/36668673
http://dx.doi.org/10.1371/journal.pcbi.1010169
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