GENERATION AND CHARACTERIZATION OF UROKINASE RECEPTOR-DEFICIENT MICE

Mice homozygously deficient for the urokinase-type plasminogen activat or (u-PA) receptor (u-PAR(- -)) were generated by homologous recombina tion in D-3 embryonic stem cells. The genomic sequences comprising exo n 2 through 5 of the u-PAR gene were replaced by the neomycin resistan ce gene, resulting in inactivation of both u-PAR splice variants. The inactivated u-PAR allele was transmitted via mendelian inheritance. an d u-PAR(- -) mice displayed normal viability, grow th, and fertility. Inactivation of u-PAR was confirmed by the absence of binding of rabbi t 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 t he jugular vein. Invasion of macrophages into the peritoneal cavity af ter thioglycollate stimulation was similar in u-PAR(- -) and u-PAR(+/) mice. u-PAR(- -) peritoneal macrophages had a threefold decreased in itial rate of u-PA-mediated plasminogen activation in vitro but degrad ed extracellular matrix proteins in vitro as efficiently as u-PAR(- -) macrophages.