Impaired brain development and reduced astrocyte response to injury in transgenic mice expressing IGF binding protein-1.

Numerous reports indicate that insulin-like growth factor-I (IGF-I) has a critical role in brain development, that it contributes to neuronal survival and that its activity is regulated by a family of IGF binding proteins (IGFBPs). In the present study, brain development was investigated in transgenic (Tg) mice that overexpress rat IGFBP-1 under the control of phosphoglycerate kinase promoter. Adult Tg mice had significantly decreased brain weight (299 +/- 17 vs. 499 +/- 11 mg), brain DNA content (684 +/- 8 vs. 810 +/- 31 microg) and brain protein (37 +/- 1 vs. 48 +/- 2 mg) compared with wild-type (Wt) mice and these deficits were already evident at birth. In Tg mice, myelin staining was generally reduced and there was a diminished thickness of the corpus callosum. The total area of hippocampus and dentate gyrus were significantly reduced by 55% and 72%, respectively. Bromodeoxyuridine labeling of proliferating cells in 3-day-old mice was markedly reduced by 41% in the dentate gyrus and by 19% in ventricular zones of Tg mice. Reactive astrogliosis reflected by morphology and glial fibrillary acidic protein expression of astrocytes in response to a mechanical lesion was substantially less in Tg compared with Wt mice. Mixed glial cell cultures from Tg animals were significantly less responsive to stimulation of proliferation by IGF-I than cultures from Wt mice. We conclude that overexpression of IGFBP-1 impairs brain development and reduces glial cell proliferation in response to injury.