Generation and characterization of urokinase receptor-deficient mice

Mice homozygously deficient for the urokinase-type plasminogen activator (u-PA) receptor (u-PAR(- -)) were generated by homologous recombination in D-3 embryonic stem cells. The genomic sequences comprising exon 2 through 5 of the u-PAR gene were replaced by the neomycin resistance gene, resulting in inactivation of both u-PAR splice variants. The inactivated u-PAR allele was transmitted via mendelian inheritance. and u-PAR(- -) mice displayed normal viability, grow th, and fertility. Inactivation of u-PAR was confirmed by the absence of binding of rabbit anti-murine u-PAR or of an aminoterminal fragment of murine u-PA (mu-PA.1-48) to u-PAR(- -) embryonic fibroblasts and macrophages. u-PAR(- -) mice displayed normal lysis of a murine plasma clot injected via the jugular vein. Invasion of macrophages into the peritoneal cavity after thioglycollate stimulation was similar in u-PAR(- -) and u-PAR(+/+) mice. u-PAR(- -) peritoneal macrophages had a threefold decreased initial rate of u-PA-mediated plasminogen activation in vitro but degraded extracellular matrix proteins in vitro as efficiently as u-PAR(- -) macrophages.