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Published June 2011 | Supplemental Material + Published
Journal Article Open

Mutual Inactivation of Notch Receptors and Ligands Facilitates Developmental Patterning


Developmental patterning requires juxtacrine signaling in order to tightly coordinate the fates of neighboring cells. Recent work has shown that Notch and Delta, the canonical metazoan juxtacrine signaling receptor and ligand, mutually inactivate each other in the same cell. This cis-interaction generates mutually exclusive sending and receiving states in individual cells. It generally remains unclear, however, how this mutual inactivation and the resulting switching behavior can impact developmental patterning circuits. Here we address this question using mathematical modeling in the context of two canonical pattern formation processes: boundary formation and lateral inhibition. For boundary formation, in a model motivated by Drosophila wing vein patterning, we find that mutual inactivation allows sharp boundary formation across a broader range of parameters than models lacking mutual inactivation. This model with mutual inactivation also exhibits robustness to correlated gene expression perturbations. For lateral inhibition, we find that mutual inactivation speeds up patterning dynamics, relieves the need for cooperative regulatory interactions, and expands the range of parameter values that permit pattern formation, compared to canonical models. Furthermore, mutual inactivation enables a simple lateral inhibition circuit architecture which requires only a single downstream regulatory step. Both model systems show how mutual inactivation can facilitate robust fine-grained patterning processes that would be difficult to implement without it, by encoding a difference-promoting feedback within the signaling system itself. Together, these results provide a framework for analysis of more complex Notch-dependent developmental systems.

Additional Information

© 2011 Sprinzak et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received November 12, 2010; Accepted April 12, 2011; Published June 9, 2011. Editor: Denis Thieffry, Ecole Normale Supérieure, France. Funding: This work was supported by US National Institutes of Health Fellowship F32GM77014 (DS, www.nih.gov), Fannie and John Hertz Foundation (AL, www. hertzfoundation.org), UCLA/Caltech Medical Scientist Training Program, NIH GM08042 (AL, mstp.healthsciences.ucla.edu), Ministerio de Ciencia e Innovacion project FIS2009-13360 (JGO, web.micinn.es), Instituto de Salud Carlos III (JGO, www.isciii.es), ICREA Academia program (JGO, www.icrea.cat), Caltech Center for Biological Circuit Design (www.cbcd.caltech.edu), and The Packard Foundation (www.packard.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Author Contributions: Conceived and designed the experiments: DS AL JGO MBE. Performed the experiments: DS AL LL JGO. Wrote the paper: DS AL JGO MBE.

Attached Files

Published - Sprinzak2011p14797Plos_Comput_Biol.pdf

Supplemental Material - Figure_S1.tif

Supplemental Material - Figure_S2.tif

Supplemental Material - Figure_S3.tif

Supplemental Material - Figure_S4.tif

Supplemental Material - Table_S1.pdf

Supplemental Material - Text_S1.pdf


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