Cis Interactions between Notch and Delta Generate Mutually Exclusive Signaling States

By D. Sprinzak, A. Lakhanpal, Lauren LeBon, Leah A. Santat, M. Fontes, G. A. Anderson, Jordi García-Ojalvo, Michael B. Elowitz. Nature, 2010

626 citations recorded by the source corpus.

The Notch–Delta signalling pathway allows communication between neighbouring cells during development. It has a critical role in the formation of ‘fine-grained’ patterns, generating distinct cell fates among groups of initially equivalent neighbouring cells and sharply delineating neighbouring regions in developing tissues. The Delta ligand has been shown to have two activities: it transactivates Notch in neighbouring cells and cis-inhibits Notch in its own cell. However, it remains unclear how Notch integrates these two activities and how the resulting system facilitates pattern formation. Here we report the development of a quantitative time-lapse microscopy platform for analysing Notch–Delta signalling dynamics in individual mammalian cells, with the aim of addressing these issues. By controlling both cis- and trans-Delta concentrations, and monitoring the dynamics of a Notch reporter, we measured the combined cis–trans input–output relationship in the Notch–Delta system. The data revealed a striking difference between the responses of Notch to trans- and cis-Delta: whereas the response to trans-Delta is graded, the response to cis-Delta is sharp and occurs at a fixed threshold, independent of trans-Delta. We developed a simple mathematical model that shows how these behaviours emerge from the mutual inactivation of Notch and Delta proteins in the same cell. This interaction generates an ultrasensitive switch between mutually exclusive sending (high Delta/low Notch) and receiving (high Notch/low Delta) signalling states. At the multicellular level, this switch can amplify small differences between neighbouring cells even without transcription-mediated feedback. This Notch–Delta signalling switch facilitates the formation of sharp boundaries and lateral-inhibition patterns in models of development, and provides insight into previously unexplained mutant behaviours.

Subfields: Cell Biology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/e36b2a3cbb1119ca500109af4247c1eeda0d26b7

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Citations in the corpus

Measuring single-cell gene expression dynamics in bacteria using fluorescence time-lapse microscopy (2011, background): “16 Once all parameters have been defined, begin image acquisition.”
Notch signaling: simplicity in design, versatility in function (2011, background): “…at least in part, from the fact that ligands activate receptors on contacting cells (trans-activation), but generally inhibit receptors expressed in the same cell (cis-inhibition) (de Celis and Bray, 1997; del Alamo et al., 2011; Micchelli et al., 1997; Miller et al., 2009; Sprinzak et al., 2010).”
Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors (2016, background): “The dose/response relationship between the ligand concentration and the receptor activation is graded, replicating a feature of the endogenous Notch signaling (Sprinzak et al., 2010) (Figure S2A).”
Defining cell types and states with single-cell genomics (2015, background): “Mathematical models describing lateral inhibition mediated by Notch-Delta interactions and the resulting changes in cell state have been experimentally validated and improved to include more members of the pathway (Collier et al. 1996; Sprinzak et al. 2010; Boareto et al. 2015).”