Nutritional regulation of IGF-I expression during brain development in mice

Although brain injury induced by undernutrition during early life is well described, the mechanisms that mediate the effects of undernutrition on brain development are not known. IGF-I plays an important role in the stimulation of postnatal somatic and brain growth. We have shown that IGF-I overexpression in brain ameliorates the effects of undernutrition on early postnatal brain growth, and thus, we postulated that alterations in IGF-I expression or action mediate the pathogenesis of malnutrition-induced brain injury. To begin to address this issue we evaluated the influence of undernutrition on brain IGF-I expression during early postnatal development in mice. Undernutrition was induced in mice by separating half of the pups in each litter from their lactating darns for a defined period each day. Pups were killed at postnatal day (P) 7, P14, P21, and P28. The changes in IGF-I mRNA were quantified by ribonuclease protection assay. At P7 IGF-I mRNA abundance in undernourished animals was increased in cerebral cortex (223% of controls), but decreased in diencephalon (36% of controls). At P14, IGF-I mRNA abundance was increased in diencephalon (230% of controls). Although there were no other statistically significant alterations of IGF-I mRNA in undernourished mice, IGF-I abundance in the cerebral cortex appeared increased at P14 (142% of controls), and in cerebellum it was consistently but modestly decreased (78 and 59% of controls) from P7 to P21, respectively. We conclude that nutrition regulates murine brain IGF-I expression in a developmentally specific fashion that is dependent on the region of expression. Importantly, the influence of undernutrition on IGF-I expression is markedly different in the brain than in liver, where nutritional deficiency profoundly decreases IGF-I expression. We speculate that the relative preservation of or increases in regional brain IGF-I expression explain, at least in part, the well-known finding that undernutrition during early postnatal development has less marked growth-retarding effects on the brain than it does on the soma.