Functions of fibroblast growth factor (FGF)-2 and FGF-5 in astroglial differentiation and blood-brain barrier permeability: evidence from mouse mutants.
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.
Reuss
Bernhard
B
Department of Neuroanatomy, IZN, University of Heidelberg, 69120 Heidelberg, Germany. bernhard.reuss@urz.uni-heidelberg.de
Dono
Rosanna
R
Unsicker
Klaus
K
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000235:genetics / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D051521:Fibroblast Growth Factor 5; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D007382:Intermediate Filaments / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D062793:Occludin; D010539:Permeability; D010750:Phosphoproteins / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
C496450:Fgf5 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D009418:S100 Proteins; D012709:Serum Albumin; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D016222:Fibroblast Growth Factor 2; D051521:Fibroblast Growth Factor 5; D005346:Fibroblast Growth Factors