Loss of Tbx1 induces bone phenotypes similar to cleidocranial dysplasia

Hum Mol Genet. 2015 Jan 15;24(2):424-35. doi: 10.1093/hmg/ddu458. Epub 2014 Sep 10.


T-box transcription factor, TBX1, is the major candidate gene for 22q11.2 deletion syndrome (DiGeorge/ Velo-cardio-facial syndrome) characterized by facial defects, thymus hypoplasia, cardiovascular anomalies and cleft palates. Here, we report that the loss of Tbx1 in mouse (Tbx1(-/-)) results in skeletal abnormalities similar to those of cleidocranial dysplasia (CCD) in humans, which is an autosomal-dominant skeletal disease caused by mutations in RUNX2. Tbx1(-/-) mice display short stature, absence of hyoid bone, failed closure of fontanelle, bifid xiphoid process and hypoplasia of clavicle and zygomatic arch. A cell-type-specific deletion of Tbx1 in osteochondro-progenitor (Tbx1(OPKO)) or mesodermal (Tbx1(MKO)) lineage partially recapitulates the Tbx1(-/-) bone phenotypes. Although Tbx1 expression has not been previously reported in neural crest, inactivation of Tbx1 in the neural crest lineage (Tbx1(NCKO)) leads to an absence of the body of hyoid bone and postnatal lethality, indicating an unanticipated role of Tbx1 in neural crest development. Indeed, Tbx1 is expressed in the neural crest-derived hyoid bone primordium, in addition to mesoderm-derived osteochondral progenitors. Ablation of Tbx1 affected Runx2 expression in calvarial bones and overexpression of Tbx1 induced Runx2 expression in vitro. Taken together, our current studies reveal that Tbx1 is required for mesoderm- and neural crest-derived osteoblast differentiation and normal skeletal development. TBX1 mutation could lead to CCD-like bone phenotypes in human.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone and Bones / abnormalities*
  • Bone and Bones / metabolism
  • Cell Differentiation
  • Cleidocranial Dysplasia / embryology
  • Cleidocranial Dysplasia / genetics
  • Cleidocranial Dysplasia / metabolism*
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Humans
  • Mesoderm / embryology
  • Mesoderm / metabolism
  • Mice
  • Mice, Knockout
  • Neural Crest / abnormalities
  • Neural Crest / embryology
  • Neural Crest / metabolism
  • Osteoblasts / cytology
  • Osteoblasts / metabolism
  • Phenotype
  • T-Box Domain Proteins / deficiency*
  • T-Box Domain Proteins / genetics


  • Core Binding Factor Alpha 1 Subunit
  • Runx2 protein, mouse
  • T-Box Domain Proteins
  • Tbx1 protein, mouse