BRAIN GROWTH-RETARDATION DUE TO THE EXPRESSION OF HUMAN INSULIN-LIKE GROWTH-FACTOR BINDING PROTEIN-1 IN TRANSGENIC MICE - AN IN-VIVO MODEL FOR THE ANALYSIS OF IGF FUNCTION IN THE BRAIN

Three lines of transgenic (Tg) mice carrying a fusion gene linking the mouse metallothionein-I promoter to a cDNA encoding human insulin-lik e growth factor binding protein-1 (hIGFBP-1) were found to express the transgene in brain. As judged by comparing Tg brain weights to those of non-transgenic littermates, adult hemizygotic Tg mice of each line exhibited brain growth retardation (16.2%, 14.4% and 8.1% reductions i n weight, respectively in each line). In two lines, total brain DNA an d protein content were decreased. Further analysis indicated that the brain growth retardation was manifested in the second week of postnata l life. Given that the insulin-like growth factors (IGFs) stimulate ce ll proliferation and/or survival in neural cultures and that hIGFBP-1, when present in a molar excess, inhibits IGF interactions with their cell surface receptors, the brain growth retardation in hIGFBP-1 Tg mi ce likely results from hIGFBP-1 inhibition of IGF-stimulated growth-pr omoting actions. These hIGFBP-1 Tg mice should prove useful in definin g IGF actions during postnatal brain maturation.