title: A Runx2 threshold for the cleidocranial dysplasia phenotype.
abstract: Cleidocranial dysplasia (CCD) in humans is an autosomal-dominant skeletal disease that results from mutations in the bone-specific transcription factor RUNX2 (CBFA1/AML3). However, distinct RUNX2 mutations in CCD do not correlate with the severity of the disease. Here we generated a new mouse model with a hypomorphic Runx2 mutant allele (Runx2(neo7)), in which only part of the transcript is processed to full-length (wild-type) Runx2 mRNA. Homozygous Runx2(neo7/neo7) mice express a reduced level of wild-type Runx2 mRNA (55-70%) and protein. This mouse model allowed us to establish the minimal requirement of functional Runx2 for normal bone development. Runx2(neo7/neo7) mice have grossly normal skeletons with no abnormalities observed in the growth plate, but do exhibit developmental defects in calvaria and clavicles that persist through post-natal growth. Clavicle defects are caused by disrupted endochondral bone formation during embryogenesis. These hypomorphic mice have altered calvarial bone volume, as observed by histology and microCT imaging, and decreased expression of osteoblast marker genes. The bone phenotype of the heterozygous mice, which have 79-84% of wild-type Runx2 mRNA, is normal. These results show there is a critical gene dosage requirement of functional Runx2 for the formation of intramembranous bone tissues during embryogenesis. A decrease to 70% of wild-type Runx2 levels results in the CCD syndrome, whereas levels >79% produce a normal skeleton. Our findings suggest that the range of bone phenotypes in CCD patients is attributable to quantitative reduction in the functional activity of RUNX2.
authors.affiliation: Department of Cell Biology, Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655-0106, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lou
authors.forename: Amjad
authors.initials: A
authors.lastname: Javed
authors.forename: Sadiq
authors.initials: S
authors.lastname: Hussain
authors.forename: Jennifer
authors.initials: J
authors.lastname: Colby
authors.forename: Dana
authors.initials: D
authors.lastname: Frederick
authors.forename: Jitesh
authors.initials: J
authors.lastname: Pratap
authors.forename: Ronglin
authors.initials: R
authors.lastname: Xie
authors.forename: Tripti
authors.initials: T
authors.lastname: Gaur
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Jones
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
mesh_terms: D000818:Animals; D001846:Bone Development; D002478:Cells, Cultured; D002968:Clavicle / Q000002:abnormalities / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D002973:Cleidocranial Dysplasia / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006132:Growth Plate / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism; D010641:Phenotype; D012886:Skull / Q000002:abnormalities / Q000196:embryology / Q000254:growth & development / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit