Pitx1 determines the morphology of muscle, tendon, and bones of the hindlimb

Dev Biol. 2006 Nov 1;299(1):22-34. doi: 10.1016/j.ydbio.2006.06.055. Epub 2006 Jul 14.


The vertebrate forelimb and hindlimb are serially homologous structures; however, their distinctive morphologies suggest that different mechanisms are associated with each limb type to give rise to limb-type identity. Three genes have been implicated in this process; T-box transcription factors Tbx5 and Tbx4, which are expressed in the forelimb and hindlimb, respectively, and a paired-type homeodomain transcription factor Pitx1, expressed in the hindlimb. To explore the roles of Pitx1 and Tbx4 in patterning the hindlimb, we have ectopically misexpressed these genes in the mouse forelimb using transgenic methods. We have developed a novel technique for visualising the structure and organisation of tissues in limbs in 3D using optical projection tomography (OPT). This approach provides unparalleled access to understanding the relationships between connective tissues during development of the limb. Misexpression of Pitx1 in the forelimb results in the transformation and translocation of specific muscles, tendons, and bones of the forelimb so that they acquire a hindlimb-like morphology. Pitx1 also upregulates hindlimb-specific factors in the forelimb, including Hoxc10 and Tbx4. In contrast, misexpression of Tbx4 in the forelimb does not result in a transformation of limb-type morphology. These results demonstrate that Pitx1, but not Tbx4, determines the morphological identity of hindlimb tissues.

MeSH terms

  • Animals
  • Body Patterning
  • Bone and Bones / embryology*
  • Carpus, Animal / embryology
  • Enhancer Elements, Genetic / genetics
  • Gene Expression
  • Gene Expression Regulation, Developmental
  • Hindlimb / embryology*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Homozygote
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Mice
  • Mice, Transgenic
  • Morphogenesis*
  • Muscle, Skeletal / embryology*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Paired Box Transcription Factors / genetics
  • Paired Box Transcription Factors / metabolism*
  • Patched Receptors
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism
  • Tarsus, Animal / embryology
  • Tendons / embryology*
  • Zinc Finger Protein Gli3


  • Gli3 protein, mouse
  • Homeodomain Proteins
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • Paired Box Transcription Factors
  • Patched Receptors
  • Prrx1 protein, mouse
  • RNA, Messenger
  • Receptors, Cell Surface
  • T-Box Domain Proteins
  • Tbx4 protein, mouse
  • Zinc Finger Protein Gli3
  • homeobox protein PITX1
  • Hox 3.6 protein, mouse