Astrocyte-specific overexpression of insulin-like growth factor-I promotes brain overgrowth and glial fibrillary acidic protein expression.

Insulin-like growth factor-I (IGF-I) is widely expressed in the central nervous system (CNS). Whereas during normal development IGF-I is expressed predominantly by neurons and to a much lesser degree by glial cells, its expression in astrocytes, and often in microglia, is increased during and/or after variety of CNS injuries. Recently we have generated a new line of IGF-I Tg mice, called IGF-I(Ast/Tet-Off) Tg mice, in which IGF-I transgene is expressed specifically in astrocytes and is tightly controlled by the tetracycline analog doxycycline. In this study we examined whether IGF-I derived from astrocytes is capable of promoting neural cell growth during development. When the IGF-I transgene is allowed to be expressed, IGF-I(Ast/Tet-Off) Tg mice exhibit markedly increases in 1) brain weight; 2) brain DNA and protein abundance; and 3) number of neurons, oligodendrocytes, and astrocytes, as well as myelination, findings similar to those observed in our other lines of Tg mice that express IGF-I transgene predominantly in neurons. Unlike Tg mice with neuron-specific IGF-I expression, which manifest marked increases in the concentrations of oligodendrocyte/myelin-specific proteins, however, IGF-I(Ast/Tet-Off) Tg mice exhibit an increase in the concentration of glial fibrillary acidic protein, an astrocyte-specific protein. Furthermore, when transgene expression is blunted, brain overgrowth in IGF-I(Ast/Tet-Off) Tg mice ceases. Our data indicate that astrocyte-derived IGF-I is capable of promoting neural cells growth in vivo. Our data also suggest that IGF-I's actions in CNS depend in part on the location of its expression and cellular microenvironment and that continuous presence of IGF-I expression is necessary for brain overgrowth.