Bone morphogenetic proteins (BMPs) drive a range of cellular processes especially in the early stages of embryonic development. This family of proteins acts as one of the most important extracellular signals in development pattern formation across the animal kingdom. Cells in embryos differentiate into different cell types in response to the concentration level of BMP. This complex process is regulated by multiple regulators that serve to tune the signal response.
Extensive experimental and computational research has been performed to analyze BMP regulation in Drosophila, a widely studied model organism, and has advanced our understanding of animal development. Because of BMP’s role in regulating cell growth and differentiation, identifying key players and their dynamic regulatory interactions in BMP gradient formation provides useful information to understand how BMP signaling works across the animal kingdom, and thus lead to potential treatment of related diseases and other clinical applications. Although extensive experimental study and system biology approaches like mathematical modeling have been done to investigate BMP regulations, there are still many unanswered questions on the functions of specific BMP regulators.
Specifically, in this study we aim to investigate the roles of two feedback regulators, Crossveinless-2 (Cv2) and Eiger (Egr). These two proteins cooperate with extracellular modulators like short gastrulation (Sog), and guide the formation of BMP signal gradient in Drosophila embryonic development. A genetic network containing Eiger which promotes BMP signaling and Cv2 antagonizing BMP signaling was identified by Gavin-Smyth et al. via experimental approaches. In this report, mathematical models were built to discover the mechanism of BMP regulation with these potential feedback loops.
In order to explore Cv-2 and Eiger's roles in formation of BMP signal gradient, in this study, we developed a mathematical model with BMPs, the intracellular messenger pMad and regulators including Eiger and Cv2 for identifying potential roles of Cv2 and Eiger. A one-dimensional spatial model representing the cross-section of a Drosophila embryo was built. In order to compare models with multiple potential proposed mechanisms, we collected and processed data from experimental research and tested six alternative models with different proposed functions of Eiger and Cv2. Then these models were compared using Pareto frontiers, a widely-used concept in multi-objective optimization. While comparing different models, we developed a comparatively easy, yet efficient way of finding the Pareto fronts.
The results support a mechanism where i) Eiger is potentially preventing BMP releasing after binding to its receptor; ii) Cv2 is intermediating BMP by forming a complex with both BMP and its receptor, thus having a potential biphasic effect on BMP signaling, similar to Cv2 in Drosophila wing disc. This finding could provide new insight into the function of Eiger and Cv2, and potentially proper directions of further study.
|Advisor:||Umulis, David M., Kinzer-Ursem, Tamara L.|
|Department:||Agricultural and Biological Engineering|
|School Location:||United States -- Indiana|
|Source:||MAI 56/03M(E), Masters Abstracts International|
|Subjects:||Applied Mathematics, Systematic, Biomedical engineering, Developmental biology|
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