Retarded skeletal development in transgenic mice with a type II collagen mutation

Abstract

Transgenic mice harboring specific mutations provide a tool for systematic studies on the effects of dominant mutations on embryonic development and growth. In the present study, several different techniques were employed to follow the development of growth abnormalities and other phenotypic consequences in the mouse litters from matings of heterozygous Del1 mice carrying six copies of a mouse type II collagen transgene with a small engineered deletion mutation. Skeletal staining of complete litters with alcian blue/alizarin red S revealed that the onset of chondrogenesis and subsequent endochondral ossification were delayed in heterozygous and homozygous Del1 embryos. The lengths, widths, and shapes of long bones were all affected. Histological and in situ hybridization analyses revealed several types of abnormalities in the epiphyseal growth plates of homozygous Del1 embryos including disorganization of growth plate architecture, abnormal appositional growth activity, an increase in the number of hypertrophic chondrocytes, a deficiency in the formation of metaphyseal cancellous bone, and development of necrotic areas in the epiphyseal heads. Many of these findings parallel those seen in human chondrodysplasias. The basic information obtained on the effects of a specific deletion mutation in the type II collagen gene on the development and growth of the transgenic embryos provides a background for testing the efficacy of novel therapeutic strategies for prevention of such growth abnormalities.