Peroxidasin is required for full viability in development and for maintenance of tissue mechanics in adults

Matrix Biol. 2023 Nov 22:S0945-053X(23)00117-8. doi: 10.1016/j.matbio.2023.11.005. Online ahead of print.ABSTRACTBasement membranes are thin strong sheets of extracellular matrix. They provide mechanical and biochemical support to epithelia, muscles, nerves, and blood vessels, among other tissues. The mechanical properties of basement membranes are conferred in part by Collagen IV (Col4), an abundant protein of basement membranes that forms an extensive two-dimensional network through head-to-head and tail-to-tail interactions. After the Col4 network is assembled into a basement membrane, it is crosslinked by the matrix-resident enzyme Peroxidasin to form a large covalent polymer. Peroxidasin and Col4 crosslinking are highly conserved throughout the animal kingdom, indicating they are important, but homozygous mutant mice have mild phenotypes. To explore the role of Peroxidasin, we analyzed mutants in Drosophila, including a new CRISPR-generated catalytic null, and found that homozygotes were mostly lethal with 13% viable escapers. Mouse mutants also show semi-lethality, with Mendelian analysis demonstrating ∼50% lethality and ∼50% escapers. Despite the strong mutations, the homozygous fly and mouse escapers had low but detectable levels of Col4 crosslinking, indicating the existence of inefficient alternative crosslinking mechanisms, probably responsible for the viable escapers. Fly mutant phenotypes are consistent with decreased basement membrane stiffness. Interestingl...
Source: Matrix Biology - Category: Molecular Biology Authors: Source Type: research