Tbx5 Buffers Inherent Left/Right Asymmetry Ensuring Symmetric Forelimb Formation

PLoS Genet. 2016 Dec 19;12(12):e1006521. doi: 10.1371/journal.pgen.1006521. eCollection 2016 Dec.


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.

MeSH terms

  • Abnormalities, Multiple / genetics
  • Abnormalities, Multiple / pathology
  • Animals
  • DNA-Binding Proteins / genetics
  • Embryo, Mammalian
  • Embryonic Development / genetics*
  • Forelimb / growth & development*
  • Gene Expression Regulation, Developmental
  • Heart Defects, Congenital / genetics
  • Heart Defects, Congenital / pathology
  • Heart Septal Defects, Atrial / genetics
  • Heart Septal Defects, Atrial / pathology
  • Humans
  • Limb Buds / growth & development
  • Limb Deformities, Congenital / genetics*
  • Limb Deformities, Congenital / pathology
  • Lower Extremity Deformities, Congenital / genetics
  • Lower Extremity Deformities, Congenital / pathology
  • Mice
  • Somites / growth & development
  • T-Box Domain Proteins / genetics*
  • Upper Extremity Deformities, Congenital / genetics
  • Upper Extremity Deformities, Congenital / pathology


  • DNA-Binding Proteins
  • T-Box Domain Proteins
  • T-box transcription factor 5

Supplementary concepts

  • Holt-Oram syndrome