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.
Ni
W
W
Department of Physiology, University of Manitoba, Winnipeg, Canada.
Rajkumar
K
K
Nagy
J I
JI
Murphy
L J
LJ
D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology*; D001921:Brain / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000209:etiology; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012016:Reference Values
D005904:Glial Fibrillary Acidic Protein; D018970:Insulin-Like Growth Factor Binding Protein 1; D004247:DNA