SKELETAL DEVELOPMENT IN TRANSGENIC MICE EXPRESSING A MUTATION AT GLY574SER OF TYPE-II COLLAGEN

Skeletal development of transgenic mice with a type II collagen mutati on was analyzed and compared with wild-type littermates, The single ba se substitution in CoI2a1 resulted in a glycine to serine mutation wit hin the helical domain and corresponded to one previously identified i n a patient with the lethal human chondrodysplasia, hypochondrogenesis (Horton et al, [1992] Proc. Natl. Acad. Sci, U,S,A, 89:4583-4587), Sk eletal staining of embryos from 14.5 through 18.5 days of gestation de monstrated a dwarf phenotype in the transgenic embryos, most notably s hort limb bones and vertebral column that was first detected at 15.5 d ays post-coitus, In addition to the reduced length, the extent of ossi fication was less in the transgenic mice, The architecture of the long bone growth plate was abnormal in the transgenic tissue, in particula r there was no discernible proliferative zone. There were few stacks o f characteristically flattened cells and the overall length of the gro wth plate in the mutant embryos was reduced, At the ultrastructural le vel, there were fewer collagen fibrils present in the transgenic mouse cartilage compared to that of wild-type littermates. Ultrastructural localization of collagen types II, IX and XI revealed a similar patter n between the transgenic and wild-type pups, suggesting that the colla gen fibrils present in the matrix of littermates with both phenotypes had a similar composition. Skeletal analysis and cartilage histochemis try indicated that effect of the type II collagen mutation was to redu ce the density of the collagen fibrils within the cartilage matrix whi ch was associated with delayed bone formation and resulted in a short- limbed phenotype. (C) 1977 Wiley-Liss, Inc.