Oxygen Levels Regulate the Development of Human Cortical Radial Glia Cells

The oxygen (O-2) concentration is a vital parameter for controlling the survival, proliferation, and differentiation of neural stem cells. A prenatal reduction of O-2 levels (hypoxia) often leads to cognitive and behavioral defects, attributable to altered neural development. In this study, we analyzed the effects of O-2 levels on human cortical progenitors, the radial glia cells (RGCs), during active neurogenesis, corresponding to the second trimester of gestation. Small changes in O-2 levels profoundly affected RGC survival, proliferation, and differentiation. Physiological hypoxia (3% O-2) promoted neurogenesis, whereas anoxia (<1% O-2) and severe hypoxia (1% O-2) arrested the differentiation of human RGCs, mainly by altering the generation of glutamatergic neurons. The in vitro activation of Wnt-beta-catenin signaling rescued the proliferation and neuronal differentiation of RGCs subjected to anoxia. Pathologic hypoxia (<= 1% O-2) also exerted negative effects on gliogenesis, by decreasing the number of O4(+) preoligodendrocytes and increasing the number of reactive astrocytes derived from cortical RGCs. O-2-dependent alterations in glutamatergic neurogenesis and oligodendrogenesis can lead to significant changes in cortical circuitry formation. A better understanding of the cellular effects caused by changes in O-2 levels during human cortical development is essential to elucidating the etiology of numerous neurodevelopmental disorders.