Mutation in type II collagen gene disturbs spinal development and gene expression patterns in transgenic Del1 mice.

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.