The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity


During embryonic development, initially similar fields can develop into distinct structures, such as the vertebrate fore- and hindlimbs. Although considerable progress has been made in our understanding of the genetic control underlying the establishment of the different limb axes1,2,3, the molecular cues that specify the differential development of the fore- and hindlimbs are unknown. Possible candidates for genes determining limb identity are Pitx1, a gene whose transcripts are detected in the early hind- but not forelimb bud, and two members of the T-box (Tbx) gene family, Tbx4 and Tbx5, which are specifically expressed in the hindlimb and forelimb buds, respectively4,5,6. Here we show that Tbx4 and Tbx5 are essential regulators of limb outgrowth whose roles seem to be tightly linked to the activity of three signalling proteins that are required for limb outgrowth and patterning: fibroblast growth factor (FGF), bone morphogenetic protein (BMP) and Wnt. In addition, we provide evidence that Tbx4 and Tbx5 are involved in controlling limb identity. Our findings provide insight into how similar developmental fields can evolve into homologous but distinct structures.

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Figure 1: Tbx5 and Tbx4 regulate limb outgrowth.
Figure 2: Feedback regulatory loops between Tbx5/4 and the FGF, WNT and BMP signalling pathways.
Figure 3: FGF and Tbx4 change the fate of anterior flank cells from wing to leg.
Figure 4: Tbx4 promotes ‘legness’.


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We thank A. Ryan and Y. Kanegae for help in the initial phase of this work; D.Büscher, J. Capdevila, J. K. Ng and A. T. Tavares for comments; C. Tabin, S. Simonet and C. Deng for unpublished results; C. Tabin, Y. Kawakami and L. T. Williams for reagents; and L. Hooks for help in preparing the manuscript. This work was supported by grants from the NSF and the G. Harold and Leila Y. Mathers Foundation to J.C.I.B., who is a Pew Scholar.

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Correspondence to Juan Carlos Izpisua Belmonte.

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Rodriguez-Esteban, C., Tsukui, T., Yonei, S. et al. The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity. Nature 398, 814–818 (1999).

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