Predictive Modeling of Signaling Crosstalk during C. elegans Vulval Development

Abstract

Caenorhabditis elegans vulval development provides an important paradigm for studying the process of cell fate determination and pattern formation during animal development. Although many genes controlling vulval cell fate specification have been identified, how they orchestrate themselves to generate a robust and invariant pattern of cell fates is not yet completely understood. Here, we have developed a dynamic computational model incorporating the current mechanistic understanding of gene interactions during this patterning process. A key feature of our model is the inclusion of multiple modes of crosstalk between the epidermal growth factor receptor (EGFR) and LIN-12/Notch signaling pathways, which together determine the fates of the six vulval precursor cells (VPCs). Computational analysis, using the model-checking technique, provides new biological insights into the regulatory network governing VPC fate specification and predicts novel negative feedback loops. In addition, our analysis shows that most mutations affecting vulval development lead to stable fate patterns in spite of variations in synchronicity between VPCs. Computational searches for the basis of this robustness show that a sequential activation of the EGFR-mediated inductive signaling and LIN-12 / Notch-mediated lateral signaling pathways is key to achieve a stable cell fate pattern. We demonstrate experimentally a time-delay between the activation of the inductive and lateral signaling pathways in wild-type animals and the loss of sequential signaling in mutants showing unstable fate patterns; thus, validating two key predictions provided by our modeling work. The insights gained by our modeling study further substantiate the usefulness of executing and analyzing mechanistic models to investigate complex biological behaviors.

Systems biology and the integration of mechanistic explanation and mathematical explanation

“…As discussed in Section 3.1, tracking the effects of (possible) manipulations is to get at causes. What many models in systems biology capture are not just manipulations at the surface, but changes of specific molecular components internal to the system, most prominently mutants whose modified genes lead to changed gene products and molecular pathways (Fisher et al, 2007). The case studies in the following section will illustrate in more detail how 'prediction' from mathematical models in systems biology often gets at the internal causal structure of biological systems and thereby offer mechanistic explanations.…”

Evolutionary Developmental Biology and the Limits of Philosophical Accounts of Mechanistic Explanation

“…The biological cases discussed in the following sections are no exception (e.g., Fisher et al 2007;Manu et al 2009b). While Craver tends to view prediction and explanation in opposition, in the below and many other cases where mathematical models are based on molecular data, the model and its predictions are to hold not only for the naturally occurring organism, but also for different experimental modifications to the organism, typically the phenotypes of various mutants.…”

“…While originally the laser ablation of individual cells was one of the primary experimental methods for investigating the causes of development and the impacts of developmental perturbations, nowadays accounts of the robustness of vulva development can rely on experimental data about molecular pathways and signaling networks (Braendle and Félix 2008;Milloz et al 2008). Based on information about gene interactions, Fisher et al (2007) present a mathematical model of vulva development, which is additionally validated by the subsequent experimental verification of two model-derived predictions (one about the wild-type, the other about a mutant). The computational model sheds light on the mechanistic basis of stable cell fate patterns as an instance of robust development.…”

What Can Formal Methods Bring to Systems Biology?

“…The complexity and universality of the biological mechanisms underlying the vulval development (e.g. cell-cell interactions, cell differentiation, cross-talk between pathways, gene regulation), and the intensive biological investigations undertaken during the last 20 years [19] make this process an extremely appealing case study [8,9,10,14,20]. In particular, the considerable amount of descriptive biological knowledge about the process joint with the lack of precise biochemical parameters, and the large number of genetic perturbations tested in vivo, welcome the research of alternative modelling procedures.…”