In culture, insulin-like growth factor-I (IGF-I) increases neuron number by stimulating progenitor proliferation and by promoting survival of neurons and their progenitors. Mice with genomic alterations in IGF-I expression or actions exhibit findings consistent with an in vivo role for IGF-I in neurogenesis and in promoting neuron survival. The investigator has generated transgenic (Tg) mouse lines that overexpress IGF-I in the brain postnatally. In these Tg mice, brain overgrowth is characterized by increases in neuron number and decreases in the number of apoptotic neurons, as well as increases in neuron cell body size and neuritic outgrowth. The IGF-I Tg mice also exhibit an increase in the number of neurons that immunostain for nestin, an intermediate filament protein expressed by neural stem cells and their progeny. In contrast, Tg mice with ectopic brain expression of IGF binding protein-I, an inhibitor of IGF action, exhibit brain growth retardation with decreased cell number, and mice with ablated IGF-I or type 1 IGF receptor (IGFlR) gene function (knock-out or KO mice) have small brains. The investigator proposes testing the hypothesis that IGF-I amplifies neuron number in vivo by inhibiting apoptosis of neural stem cells and neuron progenitors. He has three specific aims. 1) Determine IGF-I anti-apoptotic mechanisms of action in the cerebellum, a brain region whose postnatal growth is markedly stimulated by IGF-I. He will use IGF-I Tg, IGF-I KO mice and normal mice, and determine alterations in the expression and activity of known regulators of apoptosis, including selected Bcl-2 family members, inhibitor of apoptosis proteins (IAP) and caspases. 2) The investigator will determine IGF-I actions on neural stem cells in vivo by: a) defining neural stem cell apoptosis, proliferation and migration in IGF-I Tg, IGF-I KO and normal mice during postnatal development, and b) defining IGF-I actions in embryonic neurogenesis by creating: i) Tg mice that overexpress IGF-I in neural stem cells using nestin intronic regulatory elements to direct expression of IGF-I, and ii) mice in whom the IGF1R is ablated in neural stem cells using a Cre-lox strategy. In each line he will determine the number of apoptotic and proliferative neural stem cells, and map their fates. 3) He will identify genes regulated by IGF-I during neurogenesis using suppression subtractive hybridization of cDNA derived from mice with normal and altered IGF-I function.
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