The Positional Information theory proposes that a coordinate system provides information to embryonic cells about their position and orientation along a patterning axis. Cells interpret this information to produce the appropriate pattern during differentiation. In developing embryos, diffusible signals -or morphogens- have been identified and shown to generate gradients that instruct cells on their positions along patterning axes. At the molecular level, morphogen concentration generally translates into gradients of transcription factor activity that interpret the morphogen gradient. Coupling between morphogens and interpreter transcription factors has been defined for most embryonic signalling pathways, but is lacking for the fibroblast growth factor (FGF) family, despite their well characterized role as morphogens. Here, we investigate this question in developing mouse limbs, where FGFs have an instructive role in establishing proximo-distal (PD) identities. We report a gradient of Meis homeodomain transcription factors along the mouse limb bud PD axis. This gradient is antiparallel to and shaped by the inhibitory action of distal FGF on Meis expression. Elimination of Meis results in premature limb distalization due to early onset of 5´HoxA expression, proximalization of PD segmental borders, and phocomelia, a congenital condition in which all limb segments are severely hypoplastic except for the hand/foot. Our results show that Meis transcription factors interpret the FGF signalling gradient to convey positional information along the limb bud PD axis. These findings establish a new model for the generation of PD identities in the vertebrate limb and provide a molecular basis for the interpretation of FGF signal gradients during axial patterning.

The Positional Information theory proposes that a coordinate system provides information to embryonic cells about their position and orientation along a patterning axis. Cells interpret this information to produce the appropriate pattern during differentiation. In developing embryos, diffusible signals -or morphogens- have been identified and shown to generate gradients that instruct cells on their positions along patterning axes. At the molecular level, morphogen concentration generally translates into gradients of transcription factor activity that interpret the morphogen gradient. Coupling between morphogens and interpreter transcription factors has been defined for most embryonic signalling pathways, but is lacking for the fibroblast growth factor (FGF) family, despite their well characterized role as morphogens. Here, we investigate this question in developing mouse limbs, where FGFs have an instructive role in establishing proximo-distal (PD) identities. We report a gradient of Meis homeodomain transcription factors along the mouse limb bud PD axis. This gradient is antiparallel to and shaped by the inhibitory action of distal FGF on Meis expression. Elimination of Meis results in premature limb distalization due to early onset of 5´HoxA expression, proximalization of PD segmental borders, and phocomelia, a congenital condition in which all limb segments are severely hypoplastic except for the hand/foot. Our results show that Meis transcription factors interpret the FGF signalling gradient to convey positional information along the limb bud PD axis. These findings establish a new model for the generation of PD identities in the vertebrate limb and provide a molecular basis for the interpretation of FGF signal gradients during axial patterning.