ONTOGENY OF INSULIN-LIKE GROWTH FACTOR-I, ITS RECEPTOR, AND ITS BINDING-PROTEINS IN THE RAT HYPOTHALAMUS

A role for the insulin-like growth factors (IGFs) in brain growth and differentiation has recently been suggested. In previous studies on fetal hypothalamic cells we found a trophic influence of IGF-I on in vitro survival and differentiation of both neurons and glia. We have now investigated the expression of IGF-I, its receptor and its binding proteins in the rat hypothalamus to determine whether endogenous IGF-I might serve as a trophic factor during development of this brain area. Both IGF-I receptors and IGF-I binding proteins showed marked developmental stage-dependent variations. Thus, IGF-I receptors as measured by both binding and cross-linking techniques, were highest during fetal life and steadily decreased thereafter to reach low adult levels. Changes in receptor numbers rather than in its affinity constant accounted for the differences seen in binding activity during development. In addition, we found 3 different IGF-I binding proteins (IGFBPs) of apparent M(r) of 24, 29 and 32 kDa respectively, whose levels also showed a specific developmental pattern. Highest levels of the 29 and 32 kDA IGFBPs were found in fetal and early postnatal life, whereas levels of the 24 kDa form were highest in young adults. Changes in the concentration of IGFBPs rather than in their affinities for IGF-I accounted for the different binding capacities found. Using a specific IGF-I radioimmunoassay we found that IGF-I-like immunoreactivity (IGF-I-li) levels had no direct correlation with developmental stage. IGF-I-li levels oscillated with no apparent trend throughout development of the hypothalamus. Finally, when fetal hypothalamic cells were cultured in a serum-free medium and exposed at different times after seeding to IGF-I, a significant survival-promoting effect of IGF-I was found only in those cultures exposed to the trophic factor at early times after seeding. The fact that both the IGF-I receptor and its binding proteins are developmentally modulated while IGF-I is not, suggests the existence of diverse regulatory mechanisms targetted at the different molecules of this system. In addition, this complex pattern of variation of the different molecules involved in the biological effects of IGF-I support the idea that IGF-I is a physiologically relevant factor in the neurogenesis of the hypothalamus.