Authors
Lou, YangJaved, Amjad
Hussain, Sadiq
Colby, Jennifer
Frederick, Dana
Pratap, Jitesh
Xie, Ronglin
Gaur, Tripti
Van Wijnen, Andre J.
Jones, Stephen N.
Stein, Gary S.
Lian, Jane B.
Stein, Janet L.
Document Type
Journal ArticlePublication Date
2008-11-26Keywords
AnimalsBone Development
Cells, Cultured
Clavicle
Cleidocranial Dysplasia
Core Binding Factor Alpha 1 Subunit
Female
Growth Plate
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Osteoblasts
Phenotype
Skull
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
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.Source
Hum Mol Genet. 2009 Feb 1;18(3):556-68. Epub 2008 Nov 20. Link to article on publisher's site
DOI
10.1093/hmg/ddn383Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39337PubMed ID
19028669Related Resources
ae974a485f413a2113503eed53cd6c53
10.1093/hmg/ddn383