Chronic hypoxia up-regulates fibroblast growth factor ligands in the perinatal brain and induces fibroblast growth factor-responsive radial glial cells in the sub-ependymal zone.

Abstract

A number of signaling molecules have been implicated in the acute response to hypoxia/ischemia in the adult brain. In contrast, the reaction to chronic hypoxemia is largely unexplored. We used a protocol of chronic hypoxia in rat pups during the first three postnatal weeks, encompassing the period of cellular plasticity in the cerebral cortex. We find that the levels of fibroblast growth factor 1 (FGF1) and FGF2, two members of the FGF family, increase after 2 weeks of chronic hypoxia. In contrast, members of the neurotrophin family are unaffected. FGF2 is normally expressed in the nucleus of mature, glial fibrillary acidic protein (GFAP)-containing astrocytes. Under hypoxia, most FGF2-containing cells do not express detectable levels of GFAP, suggesting that chronic low O(2) induces their transformation into more immature glial phenotypes. Remarkably, hypoxia promotes the appearance of radial glia throughout the sub-ventricular and ependymal zones. Most of these cells express vimentin and brain lipid binding protein. A subset of these radial glial cells expresses FGF receptor 1, and are in close contact with FGF2-positive cells in the sub-ventricular zone. Thus, FGF receptor signaling in radial glia may foster cell genesis after chronic hypoxic damage. From the results of this study we suggest that after the chronic exposure to low levels of oxygen during development, the expression of radial glia increases in the forebrain periventricular region. We envision that astroglia, which are the direct descendants of radial glia, are reverting back to immature glial cells. Alternatively, hypoxia hinders the normal maturation of radial glia into GFAP-expressing astrocytes. Interestingly, hypoxia increases the levels of expression of FGF2, a factor that is essential for neuronal development. Furthermore, chronic hypoxia up-regulated FGF2's major receptor in the periventricular region. Because radial glia have been suggested to play a key role in neurogenesis and cell migration, our data suggests that hypoxia-induced FGF signaling in radial glia may represent part of a conserved program capable of regenerating neurons in the brain after injury.