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Transgenic Del1 mice harboring
a deletion mutation in the cartilage-specific type II collagen gene were
used for a systematic study on the dose-dependent effects of this dominant
mutation on the embryonic development and growth of the vertebral column.
Skeletal staining of homozygous and heterozygous Del1 mice and their nontransgenic
littermates with Alcian blue/Alizarin red revealed not only a dose-dependent
retardation in the appearance of ossification centers in transgene-positive
offspring but also abnormal shapes and proportions of their vertebral columns.
Histologic analysis confirmed these findings and demonstrated also retarded
removal of the notochord, abnormal shapes and sizes of vertebral bodies
and intervertebral discs, and the presence of an occult spina bifida in
homozygous Del1 mice. In situ hybridization revealed abnormalities in the
expression patterns of type I, II, IX, and X collagens and aggrecan, corresponding
to the disorganization of the columnar chondrocyte architecture of the growth
zones, increased appositional growth activity along the periphery of the
vertebrae, increased numbers of hypertrophic chondrocytes, and development
of necrotic areas in the central cartilaginous areas of vertebral bodies
of homozygous Del1 embryos. Many of these findings parallel those seen in
human chondrodysplasias and help us to understand the pathogenetic mechanisms
involved in these developmental abnormalities. |
