Figure 1. Digits initiate as regularly spaced spots.

(A) Digit formation has been modeled on the basis of Turing-like mechanisms. The classical Turing formulation is of a two component reaction-diffusion system involving an activator (A, Blue) and an inhibitor (I, red). A autoactivates itself as well as activating I, while I inhibits A. In addition, I diffuses faster than A. In this setting, slight fluctuations in initial conditions trigger self-reinforcing interactions, ultimately leading to a stable state of alternating spatial domains of activator and inhibitor activity. (B) Sox9 in situ hybridization and skeletal preparations of wild-type and compound mutant forelimb autopods (reprinted with permission from Sheth et al., 2012). (C) Initiation of digit rays as dots of precartilaginous condensations, taken from Zhu et al., 2008. (D) Initiation of digit organizing centers (red dots; PFR/DC, see main text), distal to the Hox transition zone and just underneath the AER, and subsequent fanning out of digits rays due to autopod growth patterns. Growing cartilaginous digit rays are depicted in white. Note, this diagram illustrates the relationship between the location where organizing centers form relative to proximal Hox gene expression and the process by which the digit rays are laid down as the organizing centers are displaced distally. This diagram does not incorporate the differences in the timing of condensation of the different digit organizing centers, shown in Figure 2A. (E) Spacing of developing skeletal elements, measured at their proximal base, for the Gli3/Hoxa13/Hoxd11-13 allelic series as reported in Sheth et al., 2012. (N.B. The values are those reported in Supplementary Figure 4 of Sheth et al., 2012 for digit spacing at level 1 (most proximal level in their analysis). For numbers of independent samples measured and statistical validation, please refer to that paper.) The most anterior and posterior positions were excluded from the analysis, due to the difficulty in getting reliable measurements for these elements due to curvature of the handplate at the margins. (F) Length ratios of the proximal, Sox9-negative domain (red) to the distally developing skeletal elements (yellow) in embryos of the same allelic series. (G) Distal shift in Hoxd9 expression boundary in compound mutant forelimb autopods (adapted with permission from Sheth et al., 2007).