RRC ID 77583
Author Funato N, Nakamura M, Richardson JA, Srivastava D, Yanagisawa H.
Title Loss of Tbx1 induces bone phenotypes similar to cleidocranial dysplasia.
Journal Hum Mol Genet
Abstract 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.
Volume 24(2)
Pages 424-35
Published 2015-1-15
DOI 10.1093/hmg/ddu458
PII ddu458
PMID 25209980
MeSH 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
IF 5.101
Mice RBRC01145
Human and Animal Cells COS-1(RCB0143)