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 HoltOram
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.