Three papers in this issue together show, for the first time, that the T-box transcription factors Tbx4 and Tbx5 have critically important roles in specifying limb identity and in maintaining limb outgrowth through their regulation of genes that are essential for limb development. Toshihiko Ogura and colleagues misexpressed dominant-negative forms of these genes in the prospective limb fields of chick embryos (see p. 2729). This misexpression produced limbless phenotypes, and the repression of the Wnt2b, Wnt8c, Fgf8 and Fgf10 genes. By contrast, when Tbx5 and Tbx4 were misexpressed in chick embryo flanks, additional wing- (in response to Tbx5) and leg-like (in response to Tbx4) structures were induced, accompanied by the upregulation of Wnts and Fgfs. Thus, each Tbx gene confers a specific limb identity – Txb5 the forelimb/wing and Tbx4 the hindlimb – and initiates limb development by activating a Wnt/Fgf signalling cascade, as also indicated in the accompanying papers. When Logan and colleagues conditionally inactivated Tbx5 in the developing mouse forelimb (see p. 2741), the forelimb bud completely failed to grow and Fgf10 expression was lost from the prospective forelimb bud mesenchyme, resulting in extensive apoptosis. This team also misexpressed dominant-negative and dominant-activated forms of Tbx5 in the chick wing to reveal that Tbx5 is also required at later stages of limb bud development for continued limb outgrowth. By contrast, when Papaioannou and colleagues inactivated Tbx4 in mice (see p. 2681), the initial patterning of hindlimb buds occurred normally but hindlimb development subsequently failed, in vitro and in vivo. Together these findings shed new light on a conserved genetic network that controls vertebrate limb development, and on the position and function of these Tbx genes in this network.
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