TYPE-III COLLAGEN IS CRUCIAL FOR COLLAGEN-I FIBRILLOGENESIS AND FOR NORMAL CARDIOVASCULAR DEVELOPMENT

Type III collagen is a fibrilar forming collagen comprising three alph a 1(III) chains and is expressed in early embryos and throughout embry ogenesis. In the adult, type III collagen is a major component of the extracellular matrix in a variety of internal organs and skin, Mutatio ns in the COL3A1 gene have been implicated as a cause of type IV Ehler s-Danlos syndrome, a disease leading to aortic rupture in early adult life. To directly study the role of Col3a1 in development and disease, we have inactivated the Col3a1 gene in embryonic stem cells by homolo gous recombination, The mutated allele was transmitted through the mou se germ line and homozygous mutant animals were derived from heterozyg ous intercrosses. About 10% of the homozygous mutant animals survived to adulthood but have a much shorter life span compared with wild-type mice. The major cause of death of mutant mice was rupture of the majo r blood vessels, similar to patients with type IV Ehlers-Danlos syndro me. Ultrastructural analysis of tissues from mutant mice revealed that type III collagen is essential for normal collagen I fibrillogenesis in the cardiovascular system and other organs.