Qualitative Dynamical Modelling Can Formally Explain Mesoderm Specification and Predict Novel Developmental Phenotypes.
Given the complexity of developmental networks, it is often difficult to predict the effect of genetic perturbations, even within coding genes. Regulatory factors generally have pleiotropic effects, exhibit partially redundant roles, and regulate highly interconnected pathways with ample cross-talk. Here, we delineate a logical model encompassing 48 components and 82 regulatory interactions involved in mesoderm specification during Drosophila development, thereby providing a formal integration of all available genetic information from the literature. The four main tissues derived from mesoderm correspond to alternative stable states. We demonstrate that the model can predict known mutant phenotypes and use it to systematically predict the effects of over 300 new, often non-intuitive, loss- and gain-of-function mutations, and combinations thereof. We further validated several novel predictions experimentally, thereby demonstrating the robustness of model. Logical modelling can thus contribute to formally explain and predict regulatory outcomes underlying cell fate decisions.
Aix-Marseille Université, Marseille, France.|INSERM, Marseille, France.
Abibatou
0000-0003-3831-5385
A
Mbodj
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
E Hilary
EH
Gustafson
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
Lucia
L
Ciglar
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.|Génétique Reproduction et Développement, INSERM, Clermont-Ferrand, France.
Guillaume
G
Junion
Aix-Marseille Université, Marseille, France.|INSERM, Marseille, France.
Aitor
A
Gonzalez
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
Charles
C
Girardot
Aix-Marseille Université, Marseille, France.|INSERM, Marseille, France.|CNRS, Marseille, France.
Laurent
L
Perrin
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
Eileen E M
EE
Furlong
Computational Systems Biology team, Institut de Biologie de l'Ecole Normale Supérieure (IBENS), INSERM, Ecole Normale Supérieure, PSL Research University, Paris, France.
Denis
D
Thieffry
D000818:Animals; D019295:Computational Biology; D004330:Drosophila / Q000235:genetics / Q000254:growth & development / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D008648:Mesoderm / Q000502:physiology*; D008954:Models, Biological; D009154:Mutation; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology