TY - JOUR
T1 - Computational Model of Secondary Palate Fusion and Disruption
AU - Hutson, M. Shane
AU - Leung, Maxwell C.K.
AU - Baker, Nancy C.
AU - Spencer, Richard M.
AU - Knudsen, Thomas B.
N1 - Funding Information:
This research was supported by EPA’s Office of Research and Development under the Chemical Safety for Sustainability Research Program (MCKL, NCB, TBK), the Environmental Modeling and Visualization Laboratory (RMS) and a cooperative agreement under U.S. EPA-Science To Achieve Results (STAR) Program grant # 83573601 (MSH). The authors declare that no conflicts of interest exist.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/4/17
Y1 - 2017/4/17
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.chemrestox.6b00350
DO - 10.1021/acs.chemrestox.6b00350
M3 - Article
C2 - 28045533
AN - SCOPUS:85018500801
SN - 0893-228X
VL - 30
SP - 965
EP - 979
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
IS - 4
ER -