The role of insulin-like growth factor-I (IGF-I) in cerebral cortex development.

摘要

The in vivo actions of insulin-like growth factor-I (IGF-I) on the embryonic and early postnatal development of the cerebral cortex were investigated in a line of transgenic mice that overexpress IGF-I in the brain under the control of regulatory sequences from the nestin gene. Transgene expression in these mice, designated nestin/IGF-I transgenics, begins by as early as embryonic day (E) 13 and continues into postnatal life, with the highest levels of expression detected in the cerebral cortex. To determine the effect of elevated IGF-I expression on cortex development, stereological analyses were conducted by light microscopy at postnatal day (P) 12. These analyses revealed a 31% increase in the total volume of the cerebral cortex and a corresponding 27% increase in the total number of cortical neurons in transgenic mice as compared to normal littermate controls. To investigate the mechanisms by which IGF-I overexpression promotes increased neuron number in nestin/IGF-I transgenic mice, an analysis of the cell cycle kinetics of neuron progenitors in the cerebral wall was conducted at E14, the approximate midpoint of cortical neurogenesis in normal mice (E11-E17). The lengths of the total cell cycle and all individual phases (G1, S, G2, and M) were measured in transgenic and control embryos. Total cell cycle length was decreased by 2.05 hr in transgenic embryos, due entirely to a reduction in G1 phase length. Analyses conducted to measure the proportion of cells exiting the cell cycle on E14-E15 revealed a 15% decrease in the exiting fraction of cells in transgenic embryos. A corresponding 27% increase in the proportion of Tbr2-positive intermediate progenitor cells was noted in the cerebral wall of transgenic embryos on E14. The anti-apoptotic actions of IGF-I in the cortex were assessed during early postnatal development, at P0 and P5. A significant decrease (31-39%) in the numerical density of apoptotic neurons in the cortex was documented in transgenic mice at these ages. Taken together, the results of the present set of experiments indicate that IGF-I acts both to promote neuron progenitor proliferation and to decrease neuron death by apoptosis in the developing cerebral cortex.