The fish fin bud is homologous to the limb bud and similarly has progress zone mesenchyme and an overlying apical ectodermal ridge (AER). However, after proximal patterning of the stylopod, the AER of the fin bud changes into an apical ectodermal fold (AEF) which promotes fin ray development as opposed to digits (Figure 1A). One hypothesis suggests that potential developmental delays in this AER-to-AEF transition would permit longer exposure to distal signals from the AER, enabling the progress zone mesenchyme to become increasingly permissive to autopod fates (digits). Moreover, changes in the spatial and temporal pattern of distal Hox genes may be responsible for the evolution of the tetrapod hand from the distal fin region of ancient lobe-finned fish (Schneider and Shubin 2013; Freitas and Gómez-Skarmeta 2014; Zuniga 2015). Increased numbers of cis-regulatory enhancers associated with the Hoxa/d clusters could provide one mechanism for heritable adaptation of the autopod (see Figure FDO 19.1A). In further support of this model, researchers have identified both conserved enhancers (the global control region, or GCR, and CsB) and tetrapod-specific enhancers (CsS) that are associated with early (proximal) and later (distal) Hox gene expression. In fact, mouse CsS enhancers can functionally drive reporter expression in transgenic zebrafish embryos similarly within the distalmost mesenchyme (Figure 1B-D; Freitas et al. 2012).