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K. Iwao, M. Inatani, M. Ogata-Iwao, S. Okinami, H. Tanihara; Heparan Sulfate Regulates Smad Signaling in Anterior Ocular Development. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1317.
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© ARVO (1962-2015); The Authors (2016-present)
It has been known that heparan sulfate/heparan sulfate proteoglycans bind to TGF- β superfamily ligands that play critical roles in the ocular development of mammalian eyes. We investigated the effects of heparan sulfate on downstream mediators of TGF- β superfamily signaling in anterior segment development.
We disrupted the gene of EXT1 in mice during embryogenesis because EXT1 is an indispensable enzyme for the synthesis of heparan sulfate. Floxed EXT1 mice were crossed to Wnt1-Cre transgenic mice to inactivate selectively in the migrating neural crest cells, the main components of the anterior segment in mammalian eyes.
The heparan sulfate-deficient mice exhibited various anomalies in the anterior segment including the thinning of corneal stroma, lack of corneal endothelial cells and the dysgenesis in iridocorneal angle. In heparan sulfate-deficient embryos at E13.5, the phosphorylated Smad2, the downstream mediator of TGF- β2, was downregulated in prospective chamber angle. At E15.5, the expression of the transcription factors PITX2 that plays essential for the differentiation to collagen-synthesizing keratocytes was absent in cornea, and FOXC1expression involved in the formations of corneal endothelial layer and structures of the trabecular meshwork were also affected in presumptive iridocorneal angle in the heparan sulfate-null mice. Additionally, we confirmed the binding between heparan sulfate and TGF- β2 in binding assay.
Heparan sulfate deficiency leads to the severe anomaly of the anterior segment. Our present data clearly demonstrate that heparan sulfate is essential for proper anterior segment formation to regulate differentiations of neural crest cells via Smad signal pathway.
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