Elsevier

Neuroscience

Volume 112, Issue 4, 19 July 2002, Pages 977-991
Neuroscience

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

https://doi.org/10.1016/S0306-4522(02)00060-XGet rights and content

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 O2 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.

Section snippets

Materials

The anti-serum against rat FGF2 was a generous gift from Pam Maher (Salk Institute) (Gonzales et al., 1995). The monoclonal anti-FGF1 antibody was a generous gift of Dr. Tom Maciag (Maine Center for Molecular Medicine). The polyclonal anti-FGFR-1 extracellular domain (Ab15), gift of L.T. Williams. The following antibodies were from commercial sources: monoclonal anti-FGFR-1 (Upstate Biotechnology, NY, USA); polyclonal anti-Flg (FGFR-1; Santa Cruz Biotechnology, Santa Cruz, CA, USA); mouse

FGF tissue levels increase after chronic postnatal hypoxia

To investigate the pattern of expression of the different molecular weight forms of FGF2 during postnatal development, western blot analyses were carried out in control rats after pre-absorption of FGF ligands to heparin–Sepharose beads. These analyses demonstrated that levels for each of the three molecular weight forms of FGF2 (18, 21.5 and 23 kDa), increased within the cerebral cortex over the course of postnatal development (Fig. 1). A steep increase in FGF2 levels occurred between birth

Discussion

In this study, we show that rats raised under conditions of chronic hypoxia during the early postnatal period have significantly higher levels of FGF1 and FGF2 within the brain. By contrast, chronic hypoxia does not increase the levels of the neurotrophins BDNF and NT-3. The up-regulation of FGF2 levels occurs within immature astroglia throughout the forebrain with the exception of the sub-ependymal zone. Chronic hypoxia induces the re-appearance of FGF receptors within ependymal cells, the

Acknowledgements

This work was supported by NIH Grants No. P01 NS35476, PO1 MH49351 and R01 NS37709-01A2. We wish to thank Dr. Ann Acheson and the Bioassay group at Regeneron Pharmaceuticals, for performing the ELISA, Dr. Y.-L. Li for expert technical assistance, Dr. T. Maciag and Dr. P. Maher for gifts of antibodies and Dr. A. Alvarez-Buylla, Dr. J. Leckman and Dr. L. Ment for critical discussions. We also thank anonymous reviewers for their suggestions and constructive criticism.

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