Variable accumulation of insulin-like growth factor II in mouse tissues deficient in insulin-like growth factor II receptor

The insulin-like growth factor II receptor mediates endocytosis of insulin- like growth factor II, resulting in growth factor degradation in lysosomes. This degradation is an important regulator of growth factor activity in vi vo. as shown by the phenotype of receptor deficient mice. Recent evidence s uggests that the insulin-like growth factor IT receptor functions as a tumo ur supressor in humans, and that loss of receptor function leads to increas ed levels of the growth factor in tumours. It is difficult to establish suc h a causal relationship in human tumours however, since most tumours have u ndergone several genetic changes by the time they are examined. Using mouse embryos deficient in receptor expression, and an insulin-like growth facto r II-specific radioimmunoassay, we tested the hypothesis that lack of recep tor function leads to local accumulation of insulin-like growth factor II. We found that mutant blood and skeletal muscle had excess insulin-like grow th factor II: but that mutant lungs and liver had no accumulation. Mutant h earts had less growth factor than wild-type hearts, an unexpected observati on, since the normal embryonic heart expresses very high levels of insulin- like growth factor II receptor, and mutant mice apparently die of congestiv e heart failure. The placentas of mutant mice were larger than those of wil d-type, but this did not correlate with an excess of placental insulin-like growth factor II. These results indicate that lack of insulin like growth factor II receptor can lead to local excess of the growth factor but that s uch excess is not a necessary consequence of receptor-deficiency. (C) 1999 Elsevier Science Ltd. All rights reserved.