Essential role of BMPs in FGF-induced secondary lens fiber differentiation.
It is widely accepted that vitreous humor-derived FGFs are required for the differentiation of anterior lens epithelial cells into crystallin-rich fibers. We show that BMP2, 4, and 7 can induce the expression of markers of fiber differentiation in primary lens cell cultures to an extent equivalent to FGF or medium conditioned by intact vitreous bodies (VBCM). Abolishing BMP2/4/7 signaling with noggin inhibited VBCM from upregulating fiber marker expression. Remarkably, noggin and anti-BMP antibodies also prevented purified FGF (but not unrelated stimuli) from upregulating the same fiber-specific proteins. This effect is attributable to inhibition of BMPs produced by the lens cells themselves. Although BMP signaling is required for FGF to enhance fiber differentiation, the converse is not true. Expression of noggin in the lenses of transgenic mice resulted in a postnatal block of epithelial-to-secondary fiber differentiation, with extension of the epithelial monolayer to the posterior pole of the organ. These results reveal the central importance of BMP in secondary fiber formation and show that although FGF may be necessary for this process, it is not sufficient. Differentiation of fiber cells, and thus proper vision, is dependent on cross-talk between the FGF and BMP signaling pathways.
Department of Biochemistry and Molecular Biology L224, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
Bruce A
BA
Boswell
Paul A
PA
Overbeek
Linda S
LS
Musil
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D002642:Chick Embryo; D017077:Culture Media, Conditioned; D004847:Epithelial Cells / Q000378:metabolism; D005136:Eye Proteins / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007908:Lens, Crystalline / Q000166:cytology / Q000187:drug effects / Q000196:embryology*; D051379:Mice; D008822:Mice, Transgenic; D014822:Vitreous Body / Q000378:metabolism; D038207:delta-Crystallins / Q000378:metabolism; D000099176:Noggin Protein
D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D005136:Eye Proteins; D005346:Fibroblast Growth Factors; D007381:Intermediate Filament Proteins; D038207:delta-Crystallins; D000099176:Noggin Protein; C084808:phakinin