REGULATION OF INSULIN-LIKE-GROWTH-FACTOR-I (IGF-I) GENE-EXPRESSION INBRAIN OF TRANSGENIC MICE EXPRESSING AN IGF-I-LUCIFERASE FUSION GENE

Insulin-like growth factor I (IGF-I) plays an important role in the de velopment and function of the central nervous system (CNS). Little is known, however, about the factors and mechanisms involved in regulatio n of CNS IGF-I gene expression. To facilitate our goal to define mecha nisms of IGF-I gene regulation in the CNS, we generated several lines of transgenic (Tg) mice that express firefly luciferase (LUG) under co ntrol of a 11.3-kb fragment from the 5' region of the rat IGF-I gene. Consistent with expression of the native IGF-I gene in murine brain, e xpression of the transgene predominated in neurons and astrocytes and used promoter 1, the major IGF-I promoter in the CNS and in most tissu es. Transgene messenger RNA and protein expression rapidly increased a fter birth and peaked at postnatal (P) day 4 in all brain regions stud ied. LUC activities in all regions then gradually decreased to 0.5-4% of their peak values at P31, except for the olfactory bulb, which main tained about one third of its maximal activity. Compared with litterma te controls, administration of dexamethasone decreased LUC activity an d transgenic IGF-I messenger RNA abundance, whereas GH significantly i ncreased the expression of the transgene. Addition of GH to cultured f etal brain cells from Tg mice for 12 h also increased LUC activity in a dose-dependent manner (77-388%). These results show that this IGF-I promoter transgene is expressed in a fashion similar to the endogenous IGF-I gene, and thus indicates that the transgene contains cis-elemen ts essential for developmental, GH, and glucocorticoid regulation of I GF-I gene expression in the CNS. These Tg mice should serve as an usef ul model to study mechanisms of IGF-I gene regulation in the brain.