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The Journal of Neuroscience, July 23, 2003, 23(16):6404-6412
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Functions of Fibroblast Growth Factor (FGF)-2 and FGF-5 in Astroglial Differentiation and Blood-Brain Barrier Permeability: Evidence from Mouse Mutants
Bernhard Reuss,1 Rosanna Dono,2 andKlaus Unsicker1 1Department of Neuroanatomy, IZN, University of Heidelberg, 69120 Heidelberg, Germany, and 2Department of Developmental Biology, University of Utrecht, 3584 CH Utrecht, The Netherlands
Multiple evidence suggests that fibroblast growth factors (FGFs), most prominently FGF-2, affect astroglial proliferation, maturation, and transition to a reactive phenotype in vitro, and after exogenous administration, in vivo. Whether this reflects a physiological role of endogenous FGF is unknown. Using FGF-2 and FGF-5 single- and double mutant mice we show now a region-specific reduction of glial fibrillary acidic protein (GFAP), but not of S100 in gray matter astrocytes. FGF-2 is apparently the major regulator of GFAP, because in mice deficient for FGF-2, GFAP is distinctly reduced in cortex and striatum, whereas in FGF-5-/- animals only a reduction in the midbrain tegmentum can be observed. In FGF-2-/-/FGF-5-/- double mutant animals, GFAP-immunoreactivity is reduced in all three brain regions. Cortical astrocytes cultured from FGF-2-/-/FGF-5-/- double mutant mice revealed reduced levels of GFAP, but not S100 as compared with wild-type littermates. This phenotype could be rescued by exogenous FGF-2 but not FGF-5 (10 ng/ml). Electron microscopy revealed reduced levels of intermediate filaments in perivascular astroglial endfeet. This defect was accompanied by enhanced permeability of the blood-brain barrier (BBB), as detected by albumin extravasation. Levels of the tight junction proteins Occludin and ZO-1 were reduced in blood vessels of FGF-2-/-/FGF-5-/- double mutant mice as compared with wild-type littermates. Our data support the notion that endogenous FGF-2 and FGF-5 regulate GFAP expression in a region-specific manner. The observed defect in astroglial differentiation is accompanied by a defect in BBB function arguing for an indirect or direct role of FGFs in the regulation of BBB permeability in vivo.
Key words: astrocyte; FGF; GFAP; BBB; tight junctions; occludin
Received Dec. 27, 2002; revised May. 2, 2003; accepted May. 8, 2003.
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