Making sense-data-based simulations of vertebrate limb development

Abstract

Limb bud development has been studied for decades and contributed a wealth of knowledge to our understanding of the molecular and cellular mechanisms that govern organogenesis in vertebrate embryos. However, the general regulatory paradigms that underlie the functional and structural organization of complex systems such as developing limb buds have remained largely elusive. A significant number of mathematical theories have been proposed to explain these developmental processes, but have rarely been validated by experimental analysis. In the age of systems biology, experimental and mathematical approaches have become interlinked and enable the experimental validation of computational models by molecular and genetic analysis. This in turn allows refinement of the mathematical simulations such that simulating limb bud development becomes increasingly more realistic. The resulting models not only detect inconsistencies in the interpretation of experimental data, but their predictive power facilitates identification of key regulatory interactions and definition of so-called core and accessory mechanisms. The ongoing integrative analysis of vertebrate limb organogenesis indicates that these network simulations may be suitable for in silico genetics, that is the computational modeling of complex loss-of-functions and gain-of-functions states. Such in silico genetic approaches will permit the simulation of complex mutant phenotypes tedious or impossible to generate using mouse molecular genetics.