title: Computational Model of Secondary Palate Fusion and Disruption.
abstract: Morphogenetic events are driven by cell-generated physical forces and complex cellular dynamics. To improve our capacity to predict developmental effects from chemical-induced cellular alterations, we built a multicellular agent-based model in CompuCell3D that recapitulates the cellular networks and collective cell behavior underlying growth and fusion of the mammalian secondary palate. The model incorporated multiple signaling pathways (TGFβ, BMP, FGF, EGF, and SHH) in a biological framework to recapitulate morphogenetic events from palatal outgrowth through midline fusion. It effectively simulated higher-level phenotypes (e.g., midline contact, medial edge seam (MES) breakdown, mesenchymal confluence, and fusion defects) in response to genetic or environmental perturbations. Perturbation analysis of various control features revealed model functionality with respect to cell signaling systems and feedback loops for growth and fusion, diverse individual cell behaviors and collective cellular behavior leading to physical contact and midline fusion, and quantitative analysis of the TGF/EGF switch that controls MES breakdown-a key event in morphogenetic fusion. The virtual palate model was then executed with theoretical chemical perturbation scenarios to simulate switch behavior leading to a disruption of fusion following chronic (e.g., dioxin) and acute (e.g., retinoic acid) chemical exposures. This computer model adds to similar systems models toward an integrative "virtual embryo" for simulation and quantitative prediction of adverse developmental outcomes following genetic perturbation and/or environmental disruption.
authors.affiliation: Department of Physics & Astronomy, Department of Biological Sciences and Vanderbilt Institute for Integrative Biosystem Research & Education, Vanderbilt University , Nashville, Tennessee 37235, United States.|Oak Ridge Institute for Science & Education , Oak Ridge, Tennessee 37832, United States.
authors.forename: M Shane
authors.initials: MS
authors.lastname: Hutson
authors.affiliation: Oak Ridge Institute for Science & Education , Oak Ridge, Tennessee 37832, United States.
authors.forename: Maxwell C K
authors.initials: MCK
authors.lastname: Leung
authors.affiliation: Leidos , Research Triangle Park, Durham, North Carolina 27711 United States.
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Baker
authors.affiliation: Leidos , Research Triangle Park, Durham, North Carolina 27711 United States.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Spencer
authors.affiliation: National Center for Computational Toxicology, Office of Research & Development, U.S. Environmental Protection Agency , Research Triangle Park, Durham, North Carolina 27711, United States.
authors.forename: Thomas B
authors.identifier: 0000-0002-5036-596X
authors.initials: TB
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002465:Cell Movement; D004815:Epidermal Growth Factor / Q000378:metabolism; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008954:Models, Biological; D009010:Monte Carlo Method; D010159:Palate / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D051526:Fibroblast Growth Factor 10; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor