Opposing RA and FGF signals control proximodistal vertebrate limb development through regulation of Meis genes

Vertebrate limbs develop in a temporal proximodistal sequence, with proxima l regions specified and generated earlier than distal ones. Whereas conside rable information is available on the mechanisms promoting limb growth, tho se involved in determining the proximodistal identity of limb parts remain largely unknown. We show here that retinoic acid (RA) is an upstream activa tor of the proximal determinant genes Meis1 and Meis2. RA promotes proximal ization of limb cells and endogenous RA signaling is required to maintain t he proximal Meis domain in the limb. RA synthesis and signaling range, whic h initially span the entire lateral plate mesoderm, become restricted to pr oximal limb domains by the apical ectodermal ridge (AER) activity following limb initiation. We identify fibroblast growth factor (FGF) as the main mo lecule responsible for this AER activity and propose a model integrating th e role of FGF in limb cell proliferation, with a specific function in promo ting distalization through inhibition of RA production and signaling.