The vertebrate limb is an important model for understanding developmental patterning processes. Along the proximo-distal axis, the limb is segmented into stylopod (upper limb), zeugopod (lower limb) and autopod (hand/foot) regions, marked by the expression of particular homeobox genes - Meis1/2 most proximally and Hoxa13 most distally. Fibroblast growth factor (FGF) is a key inducer of distal fate, while the role of retinoic acid (RA) in promoting proximal fate has been controversial. Miguel Torres and co-workers () now show that RA can inhibit distal identity in both chick and mouse. Distal inactivation of Meis1/2 is required for complete downregulation of RA signalling, hence permitting Hoxa13 expression to specify the autopod. Thus, opposing gradients of FGF and RA pattern the proximo-distal axis. However, distal cells only become competent to express Hoxa13 at later time points, and the authors provide evidence for a timing mechanism that involves regulation of the chromatin state. The authors therefore propose a dual mechanism for regulating proximo-distal identity: antagonistic signalling gradients and an underlying temporal constraint.
