The IGF system during growth and differentiation of the mouse

The insulin-like growth factors (IGFs) were first discovered in 1957 by Salmon and Daughaday (1957). They found that in vivo administration of growth hormone (GH) induced a serum factor capable of stimulating sulfate uptake in cartilage. In 1972 this 'sulfation factor' was renamed somatomedin (mediator of the effects of somatotropin, GH) and classified as a growth factor (Daughaday et aI., 1972). At the same time, a compound named NSILA (nonsuppressible insulin-like activity) was found (Froesch et aI., 1966). NSILA and somatomedin each stimulated glucose incorporation into fat and sulfate incorporation into cartilage (Froesch et aI., 1976). The amino acid sequence of NSILA showed 48% homology with human pro-insulin. Therefore it was called insulin-like growth factor-I (IGF-I) (Rinderknecht and Humbel, 1978a). A second bioactive insulin-like molecule appeared to be similar, but not identical, and was named IGF-II (Rinderknecht and Humbel, 1978b). Somatomedin appeared to be identical to IGF-I (Svoboda et aI., 1980). Now, over forty years later, in vivo studies, gene expression experiments, and determination of signalling pathways have provided more insight into IGF actions. IGF receptors and IGF binding proteins (IGFBPs) have been characterized (Chernausek et aI., 1981; Kasuga et aI., 1981; Brinkman et aI., 1988; Binkert et aI., 1989; Margot et aI., 1989; Shimasaki, 1989; Murphy et aI., 1990; Shimasaki, 1990; 1991a/b; Schuller et aI., 1994). This, and the recent discovery of IGFBP related proteins, have shown the complexity of the IGF system (Oh et aI., 1996). It is clear that the IGFs, together with the other IGF system compounds, playa pivotal role in body and organ development and growth. Therefore, this chapter will review in more detait characteristics of the separate components of the IGF system. Then, focus is put on the IGF system during mouse development. A summary of the data generated to elucidate the functions of the IGF system during mouse development is described

The role of the IGF axis in IGFBP-1 and IGF-I induced renal enlargement in Snell dwarf mice

Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) is generally believed to inhibit IGF action in the circulation. In contrast, IGFBP-1 has been reported to interact with cell surfaces and enhance IGF-I action locally in some tissues. Renal IGFBP-1 levels are found elevated in various conditions characterized by renal growth (e.g. diabetes mellitus, hypokalemia). To test whether IGFBP-1 is a renotropic factor, IGFBP-1 was administered alone or in combination with IGF-I to Snell dwarf mice, an in vivo model without compensatory feedback effects on growth hormone (GH) secretion. In three control groups of Snell dwarf mice, placebo, GH or IGF-I was administered. Compared with placebo, kidney weight increased in all treated groups, however, with different effects on kidney morphology. Administration of IGF-I, alone or in combination with IGFBP-1, tended to increase glomerular volume, while no changes were seen in the other groups. Administration of IGFBP-1 or IGFBP-1+IGF-I both caused dilatation of the thin limbs of Henle's loop, while GH or IGF-I administration had no visible effect. Furthermore, IGF-I administration resulted in an increased mean number of nuclei per cortical area and renal weight, whereas GH, IGF-I+IGFBP-1 or IGFBP-1 caused a decreased renal nuclei number. In situ hybridization and immunohistochemistry showed specific changes of the renal IGF system expression patterns in the different groups. Particularly, IGFBP-1 administration resulted in extensive changes in the mRNA expression of the renal IGF system, whereas the other administration regimen resulted in less prominent modifications. In contrast, administration of IGFBP-1 and IGFBP-1+IGF-I resulted in identical changes in the protein expression of the renal IGF system. Our results indicate that IGFBP-1, alone or in combination with IGF-I, demonstrated effects on the renal tubular system that differ from the effects of IGF-I