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Mice deficient in Ext2 lack heparan sulfate and develop exostoses
Dominique Stickens1, Beverly M Zak, Nathalie Rougier
1Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA.
Development (Cambridge, England)
|October 21, 2005
Summary
Hereditary multiple exostoses (HME) is caused by mutations in EXT1/EXT2 genes. Haploinsufficiency of Ext2 in mice leads to abnormal cartilage development and bone growths, revealing insights into HME pathogenesis.
Area of Science:
- Developmental Biology
- Genetics
- Skeletal Biology
Background:
- Hereditary multiple exostoses (HME) is a genetic disorder characterized by bone outgrowths.
- Mutations in EXT1 and EXT2 genes, encoding heparan sulfate chain glycosyltransferases, cause HME.
- Heparan sulfate plays a crucial role in embryonic development.
Purpose of the Study:
- To investigate the role of Ext2 in HME pathogenesis.
- To understand the function of heparan sulfate in skeletal development.
- To explore the molecular mechanisms underlying exostoses formation.
Main Methods:
- Gene targeting to create Ext2-null mice.
- Analysis of embryonic development and skeletal phenotypes in mutant mice.
- Histological examination of cartilage differentiation in long bones and costochondral joints.
Main Results:
- Homozygous Ext2-null embryos exhibited early growth arrest and gastrulation failure.
- Ext2 heterozygous mice developed ectopic bone growths (exostoses) in approximately one-third of cases.
- All heterozygous mice displayed cartilage differentiation abnormalities, including chondrocyte disorganization and premature hypertrophy, independent of hedgehog signaling.
Conclusions:
- Heparan sulfate is essential for early embryonic development.
- Ext2 haploinsufficiency causes skeletal abnormalities and exostoses formation by disrupting cartilage differentiation.
- These findings provide insights into the molecular basis of hereditary multiple exostoses.