title: Loss of Tbx1 induces bone phenotypes similar to cleidocranial dysplasia.
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.
authors.affiliation: Research Center for Medical and Dental Sciences, Human Gene Sciences Research Division, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan Department of Molecular Biology and.
authors.forename: Noriko
authors.initials: N
authors.lastname: Funato
authors.affiliation: Research Center for Medical and Dental Sciences, Human Gene Sciences Research Division, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9148, USA and.
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.affiliation: Gladstone Institute of Cardiovascular Disease and Department of Pediatrics, University of California, San Francisco, 1650 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Srivastava
authors.affiliation: Department of Molecular Biology and hiromi.yanagisawa@utsouthwestern.edu.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yanagisawa
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities* / Q000378:metabolism; D002454:Cell Differentiation; D002973:Cleidocranial Dysplasia / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009432:Neural Crest / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D020825:T-Box Domain Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C493716:Runx2 protein, mouse; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse