Abstract
Increased expression of insulin-like growth factor-I (IGF-I) in embryonic neural progenitors in vivo has been shown to accelerate neuron proliferation in the neocortex. In the present study, the in vivo actions of (IGF-I) on naturally occurring neuron death in the cerebral cortex were investigated during embryonic and early postnatal development in a line of transgenic (Tg) mice that overexpress IGF-I in the brain, directed by nestin genomic regulatory elements, beginning at least as early as embryonic day (E) 13. The areal density of apoptotic cells (N(A), cells/mm2) at E16 in the telencephalic wall of Tg and littermate control embryos was determined by immunostaining with an antibody specific for activated caspase-3. Stereological analyses were conducted to measure the numerical density (N(V), cells/mm3) and total number of immunoreactive apoptotic cells in the cerebral cortex of nestin/IGF-I Tg and control mice at postnatal days (P) 0 and 5. The volume of cerebral cortex and both the N(V) and total number of all cortical neurons also were determined in both cerebral hemispheres at P0, P5 and P270. Apoptotic cells were rare in the embryonic telencephalic wall at E16. However, the overall N(A) of apoptotic cells was found to be significantly less by 46% in Tg embryos. The volume of the cerebral cortex was significantly greater in Tg mice at P0 (30%), P5 (13%) and P270 (26%). The total number of cortical neurons in Tg mice was significantly increased at P0 (29%), P5 (29%) and P270 (31%), although the N(V) of cortical neurons did not differ significantly between Tg and control mice at any age. Transgenic mice at P0 and P5 exhibited significant decreases in the N(V) of apoptotic cells in the cerebral cortex (31% and 39%, respectively). The vast majority of these apoptotic cells (> 90%) were judged to be neurons by their morphological appearance. Increased expression of IGF-I inhibits naturally occurring (i.e. apoptotic) neuron death during early postnatal development of the cerebral cortex to a degree that sustains a persistent increase in total neuron number even in the adult animal.