title: An expanded Notch-Delta model exhibiting long-range patterning and incorporating MicroRNA regulation.
abstract: Notch-Delta signaling is a fundamental cell-cell communication mechanism that governs the differentiation of many cell types. Most existing mathematical models of Notch-Delta signaling are based on a feedback loop between Notch and Delta leading to lateral inhibition of neighboring cells. These models result in a checkerboard spatial pattern whereby adjacent cells express opposing levels of Notch and Delta, leading to alternate cell fates. However, a growing body of biological evidence suggests that Notch-Delta signaling produces other patterns that are not checkerboard, and therefore a new model is needed. Here, we present an expanded Notch-Delta model that builds upon previous models, adding a local Notch activity gradient, which affects long-range patterning, and the activity of a regulatory microRNA. This model is motivated by our experiments in the ascidian Ciona intestinalis showing that the peripheral sensory neurons, whose specification is in part regulated by the coordinate activity of Notch-Delta signaling and the microRNA miR-124, exhibit a sparse spatial pattern whereby consecutive neurons may be spaced over a dozen cells apart. We perform rigorous stability and bifurcation analyses, and demonstrate that our model is able to accurately explain and reproduce the neuronal pattern in Ciona. Using Monte Carlo simulations of our model along with miR-124 transgene over-expression assays, we demonstrate that the activity of miR-124 can be incorporated into the Notch decay rate parameter of our model. Finally, we motivate the general applicability of our model to Notch-Delta signaling in other animals by providing evidence that microRNAs regulate Notch-Delta signaling in analogous cell types in other organisms, and by discussing evidence in other organisms of sparse spatial patterns in tissues where Notch-Delta signaling is active.
authors.affiliation: Computational Science Research Center, San Diego State University, San Diego, California, United States of America; Department of Biology, San Diego State University, San Diego, California, United States of America.
authors.forename: Jerry S
authors.initials: JS
authors.lastname: Chen
authors.affiliation: Department of Biology, San Diego State University, San Diego, California, United States of America.
authors.forename: Abygail M
authors.initials: AM
authors.lastname: Gumbayan
authors.affiliation: Computational Science Research Center, San Diego State University, San Diego, California, United States of America; Department of Biology, San Diego State University, San Diego, California, United States of America.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Zeller
authors.affiliation: Computational Science Research Center, San Diego State University, San Diego, California, United States of America; Department of Mathematics and Statistics, San Diego State University, San Diego, California, United States of America.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Mahaffy
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning / Q000235:genetics* / Q000502:physiology*; D002450:Cell Communication / Q000502:physiology; D002938:Ciona intestinalis / Q000235:genetics / Q000254:growth & development / Q000502:physiology; D019295:Computational Biology; D003198:Computer Simulation; D018507:Gene Expression Regulation, Developmental; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008959:Models, Neurological; D009010:Monte Carlo Method; D009420:Nervous System / Q000166:cytology / Q000254:growth & development; D051880:Receptors, Notch / Q000502:physiology*; D011984:Sensory Receptor Cells / Q000166:cytology / Q000502:physiology; D015398:Signal Transduction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C000600417:MIRN124 microRNA, C elegans; D008565:Membrane Proteins; D035683:MicroRNAs; D051880:Receptors, Notch; C064045:delta protein