MOUSE MUTANTS LACKING THE CATION-INDEPENDENT MANNOSE 6-PHOSPHATE INSULIN-LIKE-GROWTH-FACTOR-II RECEPTOR ARE IMPAIRED IN LYSOSOMAL-ENZYME TRANSPORT - COMPARISON OF CATION-INDEPENDENT AND CATION-DEPENDENT MANNOSE 6-PHOSPHATE RECEPTOR-DEFICIENT MICE

Two proteins have been implicated in the mannose 6-phosphate dependent transport of lysosomal enzymes to lysosomes: the 300 kDa cation-indep endent and the 46 kDa cation-dependent mannose B-phosphate receptors ( CI- and CD-MPRs). The mammalian CI-MPR also mediates endocytosis and c learance of insulin-like growth factor II (IGF-II). Mutant mice that l ack the CD-MPR are viable, mice that lack the CI-MPR accumulate high l evels of IGF-II and usually die perinatally, whereas mice that lack bo th IGF-II and CI-MPR are viable. To investigate the relative roles of the MPRs in the targeting of lysosomal enzymes in vivo, we analysed th e effect of a deficiency of either MPR on lysosomal enzyme activities in animals lacking IGF-II. In CD-MPR-deficient mice, most activities w ere relatively normal in solid tissues and some were marginally elevat ed in serum. In CI-MPR-deficient mice, some enzyme activities were mod erately decreased in solid tissues and multiple enzymes were markedly elevated in serum. Finally, total levels of serum mannose 6-phosphoryl ated glycoproteins were similar to 45-fold and similar to 15-fold high er than wild type in CI- and CD-MPR-deficient mice respectively, and t here were specific differences in the pattern of these proteins when c omparing CI- and CD-MPR deficient animals. These results indicate that while lack of the CI-MPR appears to perturb lysosome function to a gr eater degree than lack of the CD-MPR, each MPR has distinct functions for the targeting of lysosomal enzymes in vivo.