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Submitted on July 14, 2004
Accepted on November 9, 2004
Departments of Physiology& Internal Medicine, University of Manitoba, Winnipeg R3E 0W3 Canada, Center of Reproductive Medicine, Shenzhen Hospital of Peking University, Shenzhen, 518036, P. R. China and Division of Endocrinology, Department of Pediatrics, Mattel Children's Hospital at UCLA, Los Angeles
* To whom correspondence should be addressed. E-mail: ljmurph{at}cc.umanitoba.ca.
Insulin-like growth (IGF)-independent effects of IGF-binding protein-3 (IGFBP-3) have been demonstrated in vitro however the physiological significance of these effects in vivo is unclear. We generated two transgenic (Tg) mice strains that overexpress a human Gly56/Gly80/Gly81-mutant IGFBP-3 cDNA. This mutant has a markedly reduced affinity for the IGFs but retains the IGF-independent effects. Serum levels of mutant IGFBP-3 were 156 ± 12 and 400 ± 24 ng/ml, in hemizygous mice of strain 5005 and 5012 respectively. When Tg and Wt mice were compared there was no reduction in birth weight, litter size or post-natal growth. Despite differences in transgene expression in various tissues, relative organ weight was similar in Tg and Wt mice with exception of brain, where a modest reduction in brain weight was observed in the high expressing 5012 lineage. There was also a significant reduction in PNCA staining cells observed in the periventricular region of the developing brain in E18 Tg embryos. In the higher expressing 5012 Tg strain, IGF-I and murine IGFBP-3 levels, marker of growth hormone action were increased. Furthermore there was a positive correlations between mutant IGFBP-3 levels and IGF-I levels, and between mutant IGFBP-3 levels and murine IGFBP-3; P = 0.002 and P < 0.001 respectively. These data indicates that overexpression of mutant IGFBP-3 is not associated with growth retardation. The higher levels of IGF-I and murine IGFBP-3 in the 5012 Tg strain suggests the possibility that the growth inhibitory effect of mutant IGFBP-3 may be compensated for by other mechanisms.
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