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Computational Modeling and Simulation of Genital Tubercle Development
Leung, Maxwell C.K., S. Hutson, A. Seifert, R. Spencer, AND T. Knudsen. Computational Modeling and Simulation of Genital Tubercle Development. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, , 1-11, (2016).
We identify the minimal molecular network that determines the outcome of male genital tubercle development in mice.
Hypospadias is a developmental defect of urethral tube closure that has a complex etiology. Here, we describe a multicellular agent-based model of genital tubercle development that simulates urethrogenesis from the urethral plate stage to urethral tube closure in differentiating male embryos. The model, constructed in CompuCell3D, implemented spatially dynamic signals from SHH, FGF10, and androgen signaling pathways. These signals modulated stochastic cell behaviors, such as differential adhesion, cell motility, proliferation, and apoptosis. Urethral tube closure was an emergent property of the model that was quantitatively dependent on SHH and FGF10 induced effects on mesenchymal proliferation and endodermal apoptosis, ultimately linked to androgen signaling. In the absence of androgenization, simulated genital tubercle development defaulted to the female condition. Intermediate phenotypes associated with partial androgen deficiency resulted in incomplete closure. Using this computer model, complex relationships between urethral tube closure defects and disruption of underlying signaling pathways could be probed theoretically in multiplex disturbance scenarios and modeled into probabilistic predictions for individual risk for hypospadias and potentially other developmental defects of the male genital tubercle.