In order to determine the effects of IGF-I in brain development in vivo, we studied the brain development of transgenic mice that overexpress rat IGFBP-1 under the control of PGK promoter. The gross morphology of the brain in the transgenic mice was not different from those wild type control mice. Brains from the IGFBP-1 transgenic mice had reduction in weight owning to decreased total brain cell numbers. Retardation of brain growth was observed at the age as early as P0 and thereafter. The markedly reduced corpus callosum thickness in transgenic mice indicates decreased axons due to the expression of transgene. The area of hippocampus and dentate gyrus were reduced in excess of the decrease in brain weight. The distribution of cholinergic neurons, astroglia and microglia were not affected by transgene expression. The cell proliferation study showed reduced proliferating brain cells in the ventricular zone (VZ), the subventricular zone (SVZ) and the developing hippocampus, and increased apoptotic cells in neonatal transgenic mice. To further examine cell proliferation in transgenic mice, we introduced a stab wound to induce a brain lesion in adult transgenic mice and wild type control. The number of reactive astroglia was significantly reduced in transgenic mice, the immunostaining intensity for glial fibrillary acidic protein (GFAP) was also decreased in transgenic m ce. These data demonstrate that the overexpression of IGFBP-1 via its inhibitory effect on IGF-I action selectively inhibit brain development. Our findings also suggest an in vivo promoting role of IGF-I on brain response to injury.