Tbx5 and Tbx4 Are Not Sufficient to Determine Limb-Specific Morphologies but Have Common Roles in Initiating Limb Outgrowth

Division of Developmental Biology, National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom.
Developmental Cell (Impact Factor: 9.71). 02/2005; 8(1):75-84. DOI: 10.1016/j.devcel.2004.11.013
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Morphological differences between forelimbs and hindlimbs are thought to be regulated by Tbx5 expressed in the forelimb and Tbx4 and Pitx1 expressed in the hindlimb. Gene deletion and misexpression experiments have suggested that these factors have two distinct functions during limb development: the initiation and/or maintenance of limb outgrowth and the specification of limb-specific morphologies. Using genetic methods in the mouse, we have investigated the roles of Tbx5, Tbx4, and Pitx1 in both processes. Our results support a role for Tbx5 and Tbx4, but not for Pitx1, in initiation of limb outgrowth. In contrast to conclusions from gene misexpression experiments in the chick, our results demonstrate that Tbx5 and Tbx4 do not determine limb-specific morphologies. However, our results support a role for Pitx1 in the specification of hindlimb-specific morphology. We propose a model in which positional codes, such as Pitx1 and Hox genes in the lateral plate mesoderm, dictate limb-specific morphologies.

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Article: Tbx5 and Tbx4 Are Not Sufficient to Determine Limb-Specific Morphologies but Have Common Roles in Initiating Limb Outgrowth

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    • "Wnt and Fgf signaling also have important roles in the initiation of both fore-and hindlimb outgrowth, but interactions among these pathways differ to some degree in the fore-and hindlimbs (Sekine et al. 1999; Takeuchi et al. 2003; Cooper et al. 2011). As mentioned in the previous section, Tbx5's role in initial outgrowth and patterning is limited to the forelimb, while Tbx4 and Pitx1's role is restricted to the hindlimb (Rodriguez-Esteban et al. 1999; Takeuchi et al. 2003; Minguillon et al. 2005; Naiche and Papaioannou 2007; Ouimette et al. 2010). The result of this is that Tbx4 and Pitx1 only contribute to the hindlimb networks for initiation (Fig. 4) and patterning (Fig. 5), while Tbx5 only contributes to the forelimb networks. "
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    • " the genome of the extant cephalochordate amphioxus ( Ruvinsky et al . , 2000 ; Horton et al . , 2008 ) . Interestingly , in this finless chordate Tbx4 / 5 is expressed in the ventral mesoderm , suggested as a precursor of the LPM in vertebrates ( Horton et al . , 2008 ) . Moreover , this amphioxus gene is able to induce limbs in transgenic mice ( Minguillon et al . , 2005 ; Horton et al . , 2008 ) . Thus , the fin‐inducing properties of Tbx4 / 5 probably predate its duplication in vertebrates . However , regionalization into CM and PLPM may have been mandatory for the activation of its function as fin inducer ( Fig . 2A , B ; Onimaru et al . , 2011 ) . Lampreys offer a challenge to test these hypotheses "
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    • "However, more recent research suggests that the paralogs have actually ''subfunctionalized'', resulting in their differential expression in the emerging limb buds. It so happens that they both have a common role in initiating outgrowth, but not in determining limb-specific morphologies and identities as was once thought (Minguillon et al. 2005b). Loss of Tbx4 during later limb outgrowth produces no limb defects, revealing only a brief developmental requirement for its function (Naiche and Papaioannou 2007). "
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