Bare Bones Pattern Formation: A Core Regulatory Network in Varying Geometries Reproduces Major Features of Vertebrate Limb Development and Evolution

Abstract

BackgroundMajor unresolved questions regarding vertebrate limb development concern how the numbers of skeletal elements along the proximodistal (P-D) and anteroposterior (A-P) axes are determined and how the shape of a growing limb affects skeletal element formation. There is currently no generally accepted model for these patterning processes, but recent work on cartilage development (chondrogenesis) indicates that precartilage tissue self-organizes into nodular patterns by cell-molecular circuitry with local auto-activating and lateral inhibitory (LALI) properties. This process is played out in the developing limb in the context of a gradient of fibroblast growth factor (FGF) emanating from the apical ectodermal ridge (AER).ResultsWe have simulated the behavior of the core chondrogenic mechanism of the developing limb in the presence of an FGF gradient using a novel computational environment that permits simulation of LALI systems in domains of varying shape and size. The model predicts the normal proximodistal pattern of skeletogenesis as well as distal truncations resulting from AER removal. Modifications of the model's parameters corresponding to plausible effects of Hox proteins and formins, and of the reshaping of the model limb, bud yielded simulated phenotypes resembling mutational and experimental variants of the limb. Hypothetical developmental scenarios reproduce skeletal morphologies with features of fossil limbs.ConclusionsThe limb chondrogenic regulatory system operating in the presence of a gradient has an inherent, robust propensity to form limb-like skeletal structures. The bare bones framework can accommodate ancillary gene regulatory networks controlling limb bud shaping and establishment of Hox expression domains. This mechanism accounts for major features of the normal limb pattern and, under variant geometries and different parameter values, those of experimentally manipulated, genetically aberrant and evolutionary early forms, with no requirement for an independent system of positional information.

Shared rules of development predict patterns of evolution in vertebrate segmentation

“…Our results contribute to increasing evidence that activator-inhibitor interactions are involved in limb, digit and somite segmentation, and could reflect a universal design principle 4,[30][31][32][33][34][35] , but while confirmatory these results do not clarify the identity of the molecule(s) or the exact developmental mechanisms involved. We argue that the value of using the IC model is that, while previous models describe how segments form, they make no predictions about how they vary in size, and imply that elements are either independently formed or that segment proportions are largely the result of selection on later developmental events such as growth.…”

‘Biogeneric’ developmental processes: drivers of major transitions in animal evolution

“…the BSW versus two-galectin networks) in all tetrapods, and how the developing limb's gradients of Hox transcription factors modulate the Turing-type system to generate elements that are biologically customized rather than the uniform stripes dictated by purely generic reaction -diffusion mechanisms [90,91]. What seems clear, however, is that the range of skeletal patterns seen throughout sarcopterygian evolution and in experimental and mutational variants in present-day tetrapods is consistent with determination by a Turing-type system under different parameter regimes [74].…”

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

“…The spatial pattern resulting from the operation of biological processes involving nonlinear interactions (as in the case of activator-inhibitor systems) cannot be predicted from the qualitative organization of the system's components, so that some equations are explanatorily necessary (criterion ER from Section 7.3). Zhu et al (2010) present a mathematical model of limb development which not only replicates the normal development of the basic skeletal features of the chicken wing, but also different instances of modified development, including the experimental removal of the apical ectodermal ridge (a causally crucial zone at the tip of the growing limb bud) at different points in early development, and the expansion of the early limb bud either by tissue graft or as seen in two different genetic mutants. This indicates that the mathematical model gets at some causalmechanistic aspects of the actual phenomenon studied.…”

“…In any case, the attempt to capture the effects of interventions shows that the model is meant to be explanatory (see the discussion from Section 7.3). With their model, Zhu et al (2010) are able to generate several quite different fin skeletal patterns known only from distinct taxa of fossil fish.…”