Dynamic and self-regulatory interactions among gene regulatory networks control vertebrate limb bud morphogenesis

Vertebrate limb bud outgrowth and patterning is controlled by two instructive signaling centers, the apical ectodermal ridge (AER) and the polarizing region in the posterior limb bud mesenchyme. Molecular analysis of limb bud development has identified a self-regulatory signaling system that operates between the AER and mesenchyme and orchestrates the dynamic progression of limb bud outgrowth and patterning. The first focus of this review are the gene regulatory networks (GRNs) and interactions that control the positioning of the fore- and hindlimb fields along the primary body axis, establish the initial axis polarity and control the precise positioning of the signaling centers. These early processes are largely controlled by activating and inhibiting interactions among types of transcriptional regulators expressed in specific territories. The second focus deals with the dynamic interactions among the GRNs that control limb bud patterning and outgrowth by responding to inputs from the self-regulatory limb bud signaling system. The final part describes the GRN interactions regulating digit morphogenesis and the Turing-type system that controls the periodicity of the digit ray pattern. This review highlights the significant progress made toward an integrative analysis and understanding of the morpho-regulatory systems that orchestrate patterning and outgrowth of vertebrate limb buds in time and space.