Abstract
Contact of developing sensory organs with the external environment is established via the formation of openings in the skin. During eye development, eyelids first grow, fuse and finally reopen, thus providing access for visual information to the retina. Here, we show that eyelid opening is strongly inhibited in transgenic mice overexpressing the bone morphogenetic protein (BMP) antagonist noggin from the keratin 5 (K5) promoter in the epidermis. In wild-type mice, enhanced expression of the kinase-inactive form of BMPR-IB mediated by an adenovirus vector also inhibits eyelid opening. Noggin overexpression leads to reduction of apoptosis and retardation of cell differentiation in the eyelid epithelium, which is associated with downregulation of expression of the apoptotic receptors (Fas, p55 kDa TNFR), Id3 protein and keratinocyte differentiation markers (loricrin, involucrin). BMP-4, but not EGF or TGF-alpha, accelerates opening of the eyelid explants isolated from K5-Noggin transgenic mice when cultured ex vivo. These data suggest that the BMP signaling pathway plays an important role in regulation of genetic programs of eyelid opening and skin remodeling during the final steps of eye morphogenesis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenoviridae / genetics
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Adenoviridae / metabolism
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Animals
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Apoptosis / physiology*
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Biomarkers
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Bone Morphogenetic Protein Receptors
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Bone Morphogenetic Proteins / antagonists & inhibitors
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Bone Morphogenetic Proteins / metabolism
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Carrier Proteins
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Cell Differentiation / physiology*
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Culture Techniques
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DNA-Binding Proteins / metabolism
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Embryo, Mammalian / anatomy & histology
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Embryo, Mammalian / physiology
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Epidermal Cells*
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Epidermal Growth Factor / metabolism
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Epidermis / growth & development
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Epidermis / physiology
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Eyelids / cytology
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Eyelids / growth & development*
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Genetic Vectors
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Growth Differentiation Factor 5
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Humans
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In Situ Hybridization
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In Situ Nick-End Labeling
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Keratin-15
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Keratin-5
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Keratinocytes / cytology
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Keratinocytes / physiology
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Keratins / genetics
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Mice
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Mice, Transgenic
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Morphogenesis / physiology
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Neoplasm Proteins / metabolism
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Promoter Regions, Genetic
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Proteins / genetics
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Proteins / metabolism*
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Receptors, Growth Factor / genetics
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Receptors, Growth Factor / metabolism
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Signal Transduction / physiology
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Smad Proteins
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Trans-Activators / metabolism
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Transforming Growth Factor alpha / metabolism
Substances
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Biomarkers
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Bone Morphogenetic Proteins
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Carrier Proteins
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DNA-Binding Proteins
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GDF5 protein, human
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Gdf5 protein, mouse
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Growth Differentiation Factor 5
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KRT5 protein, human
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Keratin-15
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Keratin-5
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Krt15 protein, mouse
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Neoplasm Proteins
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Proteins
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Receptors, Growth Factor
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Smad Proteins
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Trans-Activators
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Transforming Growth Factor alpha
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noggin protein
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Epidermal Growth Factor
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Keratins
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Bone Morphogenetic Protein Receptors