The patterning of many developing tissues is controlled by gradients of morphogens. A significant challenge for morphogen gradients is to produce patterns that are not easily altered by genetic or environmental perturbations. The kinds of perturbations most likely to have driven the evolution of morphogen gradient systems are those that organisms face frequently: changes in biochemistry and physiology due to fluctuations in temperature, alterations in nutritional status, and the stochasticity of gene expression. Such perturbations are multifactorial, i.e. they affect many gene products and processes at the same time. Although investigators have recently begun to explore how morphogen gradients might withstand changes in the expression levels of single genes, our preliminary studies suggest that achieving robustness to multifactorial perturbations may require fundamentally different strategies. We will investigate this question through a combination of mathematical, computational and experimental approaches. Work will focus on 1 of the best-characterized morphogen gradients, the BMP gradient that patterns the larval insect wing disc. Initially, we will use both modeling and experiments to explore how this gradient responds to combinations of genetic perturbations, in order to identify rules that govern """"""""robustness tradeoffs"""""""". Next, we will test the hypothesis that the architecture of the BMP gradient system reflects a drive toward optimization of robustness to temperature fluctuations. Third, we will identify ways in which the complex regulatory architecture of the Jbrin/cer gene, a key downstream target of the BMP gradient, contributes to robustness of the overall system. Finally, we will identify ways in which the deployment of 2 BMP ligands-decapentaplegic (Dpp) and glass bottom boat (Gbb) in the same gradient system also contributes to the robustness of patterning. Understanding the strategies used by morphogen gradient systems to withstand real-world perturbations is critical for explaining why human development proceeds so accurately most of the time, and is a necessary first step toward a general understanding of how and why failures of normal development, i.e. birth defects, arise. ? ? ?
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