Figure 4. Mathematical modeling suggests that directed cell migration plays a role in the formation of the IET.

(A) Schematic representations of two proposed models for interdigital epithelial tongue formation during digit separation. Model 1: interdigital mesenchymal regression by cell death and active cell proliferation of epithelial cells in the overlying epidermis. Model 2: in addition to the factors in model 1, active cell migration of epithelial cells at the leading-edge is present. (B-C) The computational model simulating embryonic hand development during the span of 48 hours. Cells are represented by points connected by generalized Morse potentials to model biomechanical forces. Epithelial cells (pink), Periderm cells (light pink), and Mesenchymal cells (grey). (B) Model 1: Epithelial cell proliferation alone is insufficient to induce IET formation. (C) Model 2: Active cell migration (indicated by the green line at the bottom), in addition to cell proliferation, is sufficient for the epithelial to invade the cavity between the two digits and form the interdigital epithelial tongue. (D) E-cadherin staining of interdigital epithelial in WT forelimb sections at E14.5 suggests that active cell migration is indeed present in the developing limb. (E) Bright-field images of ex-vivo cultured forelimbs from E13.5 embryos at 0hrs (top) and 15hrs (bottom) of Mitomycin-C (Mito C) and Cytochalasin-D (Cyto D) treatment (N=3/group). Control group was incubated with media alone. (F) Measurements of the interdigital indentation at 15hrs post-incubation. Values were normalized to the interdigital indentation at 0hrs. Statistical significance was determined using one-way ANOVA (*p=0.01).