Human Molecular Genetics Advance Access published online on November 20, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn383
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A Runx2 Threshold for the Cleidocranial Dysplasia Phenotype
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Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655
* Address Correspondence to: Janet L. Stein, Ph.D., Department of Cell Biology, Worcester, MA 01655-0106, USA, Tel: 508-856-5625 / fax: 508-856-6800, Email: janet.stein{at}umassmed.edu, jane.lian{at}umassmed.edu
Received May 23, 2008; Revised October 9, 2008; Accepted November 10, 2008
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 severity of the disease. Here we generated a new mouse model with a hypomorphic Runx2 mutant allele (Runx2neo7), in which only part of the transcript is processed to full-length (wild-type) Runx2 mRNA. Homozygous Runx2neo7/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. Runx2neo7/neo7mice 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 deceased 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 formation of intramembranous bone tissues during embryogenesis. A decrease to 70% of wild-type Runx2 levels results in the CCD syndrome, while levels above 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.
The first two authors should be regarded as joint First Authors.
Current address: Institute of Oral Health Research, School of Dentistry, University of Alabama at Birmingham, AL 35294
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