Figure 4.

Genes implicated in the specification of the limb field during development of mouse embryos. Retinoic acid signaling is involved in the regionalization of the LPM into the ALPM and PLPM. In the PLPM, Tbx5 and Tbx4, which are expressed in forelimb- and hindlimb-forming regions, respectively, play pivotal roles in limb initiation. Nested expression of Hox genes seems to be involved in the regionalization of the PLPM into forelimb, interlimb flank and hindlimb fields. In the forelimb level, rostrally expressed Hox proteins, retinoic acid signaling and β-catenin signaling cooperatively activate Tbx5 transcription. Whereas caudally expressed Hox genes repress Tbx5 to restrict its expression to the forelimb level, Hox genes and Pitx1 have been suggested to activate Tbx4 expression at the hindlimb level. Islet1 is also required for hindlimb initiation. Islet1 is required for the nuclear accumulation of β-catenin, and β-catenin is required for the maintenance of Islet1 expression. In the forelimb posterior domain, Hox9 genes are required to trigger Hand2 expression in this region. In the forelimb anterior domain, Hox5 genes and Plzf cooperatively mediate repression of Shh expression. In the hindlimb posterior domain, Islet1 activates Hand2 expression. It should be noted that the roles of Hox genes, RA signaling and β-catenin signaling are disputed. See text for references and details.