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
Source: PubMed


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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Available from: Malcolm Logan, Aug 12, 2015
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    • "The restricted expression domains of Tbx5 and Tbx4 in the forelimb and the hindlimb, respectively, suggest that these genes could play an active role in determining forelimb and hindlimb morphologies and this was supported by some experiments in the chick [24] [25]. Gene deletion–gene replacement experiments in mouse embryos, however, clearly demonstrated that Tbx5 and Tbx4 have equivalent roles in the initiation of limb outgrowth and do not control limb-type specific morphology [26]. Ectopic expression of Tbx4 in the Tbx5 mutant forelimb can rescue forelimb formation in the absence of Tbx5 activity demonstrating that Tbx4 can produce forelimb features and Tbx5 is not required for forelimb structures to form. "
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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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