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Insulin-Like Growth Factor I (IGF-I) Regulates IGF Binding Protein-5 Gene Expression in the Brain¹

Department of Pediatrics, Division of Endocrinology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7220

Address all correspondence and requests for reprints to: A. Joseph D’Ercole, M.D., The University of North Carolina, Department of Pediatrics, Division of Endocrinology, CB 7220, 509 Burnett-Womack, Chapel Hill, North Carolina 27599-7220.

Insulin-like growth factor (IGF-I) plays an important role during brain development. IGF binding protein-5 (IGFBP-5) is known to be capable of modulating IGF-I actions and is expressed in brain during development. To begin to investigate the interaction between IGF-I and IGFBP-5 in brain, we asked whether IGF-I influences the brain expression of IGFBP-5. We quantified IGFBP-5 expression in multiple brain regions of two lines of IGF-I transgenic (Tg) mice that exhibit distinctive patterns of brain transgene expression. MT-I/IGF-I Tg mice carry a transgene driven by metallothionein-I (MT-I) promoter and exhibit highest levels of transgene expression in cerebral cortex, whereas in IGF-II/IGF-I Tg mice the mouse IGF-II promoter drives the transgene and the expression is highest in the cerebellum. In normal adult mice, IGFBP-5 messenger RNA (mRNA) was detected in all brain regions examined, and the highest levels of the mRNA were found in cerebellum, followed by brainstem, diencephalon, hippocampus, and cerebral cortex. Compared to these littermate controls, IGFBP-5 mRNA abundance was increased in both lines of Tg mice. In MT-I/IGF-I Tg mice, cerebral cortex had the greatest increase (200%), whereas cerebella of IGF-II/IGF-I Tg mice had the greatest increase in IGFBP-5 mRNA (350%). The increase in IGFBP-5 mRNA correlated with the regional expression of the transgene during development. The abundance of IGFBP-5 protein was also found to be increased in both IGF-I Tg mouse lines. The influence of IGF-I on IGFBP-5 expression was specific because we found no evidence of changes in IGFBP-2, IGFBP-4, or cyclophilin expression. Furthermore, as judged by in situ hybridization histochemistry, IGF-I appeared to increase both the number of IGFBP-5-expressing cells and the magnitude of their expression, an observation that was especially marked in the molecular layer and white matter of the cerebellum. These data indicate that IGF-I regulates IGFBP-5 expression in vivo and is consistent with the in situ hybridization data of others showing that IGFBP-5 expression is temporally and spatially related to that of IGF-I.

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