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W.Y. Kao, Y. Hayashi, C. Liu, C.W. Kao, M. Hayashi, J.L. Funderburgh, P.J. Roughley, I. Wang, S. Saika, J.V. Jester; Excess Biglycan Blocks TGF Signaling for Eyelid Morphogenesis during Development of Kera-Bgn Transgenic Mice . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2143.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Tissue morphogenesis during development involves constant remodeling of extracellular matrix and signal transduction. In present studies, we examined the effects of excess biglycan on eyelid morphogenesis during mouse development. Methods: Transgenic mice over expressing biglycan by keratocan promoter (Bgn-tg) were subjected to morphological examinations using HE staining, TUNEL assay, and BrdU incorporation, and immunohistochemistry by light, confocal and scan electron microscopy; and molecular and biochemical analysis for the expression of biglycan, α-smooth muscle actin. Biglycan and neutralizing antibodies against TGFα, TGFß, activin ßB and EGFR were included in the medium of an in vitro assay of mesenchymal cell migration induced by eyelid epithelium. Results: Adult Bgn-tg mice exhibit eyelid malformation characteristics of exposure keratitis: 1. thin eyelid stroma with fewer eyelid stromal cells, 2. premature eye opening due to non-infectious eyelid ulceration, 3. absence of Meibomian glands, 4. no enhanced apoptosis nor decreased cell proliferation. In Bgn-tg mice actin stress fiber was under developed in mesenchymal cells and malformation of orbicularis oculi muscle as revealed by confocal microscopy using anti-α smooth muscle actin antibody in comparison to those of wild type littermates. In vitro analysis revealed that biglycan, and anti-TGFα and -EGFR antibodies effectively inhibit mesenchymal cells migration induced by eyelid epithelium. Western blot analysis with anti-biglycan antibodies of immune precipitates of neutralizing antibodies indicates biglycan binds to TGFα. Conclusions Our observations suggest that during embryonic development excess biglycan sequesters TGFα and impairs eyelid morphogenesis via perturbation of the migration of periocular mesenchymal cells of neural crest origin and the differentiation of orbicularis oculi muscle.
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