Abstract
The forelimbs and hindlimbs of vertebrates are bilaterally symmetric. The mechanisms that ensure symmetric limb formation are unknown but they can be disrupted in disease. In Holt-Oram Syndrome (HOS), caused by mutations in TBX5, affected individuals have left-biased upper/forelimb defects. We demonstrate a role for the transcription factor Tbx5 in ensuring the symmetric formation of the left and right forelimb. In our mouse model, bilateral hypomorphic levels of Tbx5 produces asymmetric forelimb defects that are consistently more severe in the left limb than the right, phenocopying the left-biased limb defects seen in HOS patients. In Tbx hypomorphic mutants maintained on an INV mutant background, with situs inversus, the laterality of defects is reversed. Our data demonstrate an early, inherent asymmetry in the left and right limb-forming regions and that threshold levels of Tbx5 are required to overcome this asymmetry to ensure symmetric forelimb formation.
Highlights
The external body plan of most metazoans is bilaterally symmetric
The authors of this study demonstrate, using a mouse model, that bilateral symmetry of the arms is not a default, passive state but that mechanisms are in place that ensure symmetrical formation of the left and right limbs
Bilateral symmetry of the arms is achieved by the action of a gene Tbx5 that masks the effects of signals that acted earlier during embryogenesis, many days before limb formation, and imposed asymmetries on the forming internal organs
Summary
The external body plan of most metazoans is bilaterally symmetric. How this symmetry is achieved has fascinated biologists for centuries and is exemplified by Leonardo Da Vinci’s description of the “Vitruvian Man” that describes some of the uniform proportions of the human body. External bilateral symmetry masks significant internal asymmetries such as the position of the heart and liver and number of lobes of the lungs. While there has been progress in identifying how asymmetry of internal organs is generated [1], we know very little about how symmetry in bilateral structures, such as the limbs is established. HOS is a dominant disorder and heterozygous affected individuals carry mutations in TBX5 predicted to result in truncated proteins that fail to fold or are rapidly degraded [4] and are most likely loss-of-function alleles. HOS defects are thought to arise as a result of TBX5 haploinsufficiency and indicate that both copies of the gene are required for normal function
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