Conserved regulation of proximodistal limb axis development by Meis1/Hth

Vertebrate limbs grow out from the flanks of embryos, with their main axis extending proximodistally from the trunk. Distinct limb domains, each with specific traits, are generated in a proximal-to-distal sequence during deve lopment(1). Diffusible factors expressed from signalling centres promote th e outgrowth of limbs and specify their dorsoventral and anteroposterior axe s(2-4). However, the molecular mechanism by which limb cells acquire their proximodistal (P-D) identity is unknown(1). Here we describe the role of th e homeobox genes Meis1/2 and Pbx1 in the development of mouse, chicken and Drosophila limbs. We find that Meis1/2 expression is restricted to a proxim al domain, coincident with the previously reported domain in which Pbx1 is localized to the nucleus(5), and resembling the distribution of the Drosoph ila homologues homothorax (hth)(5,6) and extradenticle (exd)(7); that Meis1 regulates Pbx1 activity by promoting nuclear import of the Pbx1 protein; a nd that ectopic expression of Meis1 in chicken and hth in Drosophila disrup ts distal limb development and induces distal-to-proximal transformations. We suggest that restriction of Meis1/Hth to proximal regions of the vertebr ate and insect limb is essential to specify cell fates and differentiation patterns along the P-D axis of the limb.