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PMID:12878680

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Citation

Reuss, B, Dono, R and Unsicker, K (2003) Functions of fibroblast growth factor (FGF)-2 and FGF-5 in astroglial differentiation and blood-brain barrier permeability: evidence from mouse mutants. J. Neurosci. 23:6404-12

Abstract

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.

Links

PubMed

Keywords

Animals; Astrocytes/cytology; Astrocytes/metabolism; Blood-Brain Barrier/genetics; Blood-Brain Barrier/physiology; Brain/cytology; Brain/metabolism; Cell Differentiation/physiology; Fibroblast Growth Factor 2/metabolism; Fibroblast Growth Factor 5; Fibroblast Growth Factors/metabolism; Gene Expression Regulation/physiology; Glial Fibrillary Acidic Protein/genetics; Glial Fibrillary Acidic Protein/metabolism; Intermediate Filaments/metabolism; Membrane Proteins/biosynthesis; Mice; Mice, Knockout; Mice, Mutant Strains; Permeability; Phosphoproteins/biosynthesis; RNA, Messenger/metabolism; S100 Proteins/metabolism; Serum Albumin/metabolism; Tight Junctions/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:GFAP

located_in

GO:0005882: intermediate filament

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FGF2

acts_upstream_of_or_within

GO:0010001: glial cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2384003

P

Seeded From UniProt

complete

MOUSE:FGF5

acts_upstream_of_or_within

GO:0010001: glial cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1857847

P

Seeded From UniProt

complete

MOUSE:GFAP

part_of

GO:0005882: intermediate filament

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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