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Heparan sulfate deficiency leads to Peters anomaly in mice by disturbing neural crest TGF-β2 signaling
Keiichiro Iwao, … , Satoshi Okinami, Hidenobu Tanihara
Keiichiro Iwao, … , Satoshi Okinami, Hidenobu Tanihara
Published June 8, 2009
Citation Information: J Clin Invest. 2009;119(7):1997-2008. https://doi.org/10.1172/JCI38519.
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Research Article Ophthalmology

Heparan sulfate deficiency leads to Peters anomaly in mice by disturbing neural crest TGF-β2 signaling

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Abstract

During human embryogenesis, neural crest cells migrate to the anterior chamber of the eye and then differentiate into the inner layers of the cornea, the iridocorneal angle, and the anterior portion of the iris. When proper development does not occur, this causes iridocorneal angle dysgenesis and intraocular pressure (IOP) elevation, which ultimately results in developmental glaucoma. Here, we show that heparan sulfate (HS) deficiency in mouse neural crest cells causes anterior chamber dysgenesis, including corneal endothelium defects, corneal stroma hypoplasia, and iridocorneal angle dysgenesis. These dysfunctions are phenotypes of the human developmental glaucoma, Peters anomaly. In the neural crest cells of mice embryos, disruption of the gene encoding exostosin 1 (Ext1), which is an indispensable enzyme for HS synthesis, resulted in disturbed TGF-β2 signaling. This led to reduced phosphorylation of Smad2 and downregulated expression of forkhead box C1 (Foxc1) and paired-like homeodomain transcription factor 2 (Pitx2), transcription factors that have been identified as the causative genes for developmental glaucoma. Furthermore, impaired interactions between HS and TGF-β2 induced developmental glaucoma, which was manifested as an IOP elevation caused by iridocorneal angle dysgenesis. These findings suggest that HS is necessary for neural crest cells to form the anterior chamber via TGF-β2 signaling. Disturbances of HS synthesis might therefore contribute to the pathology of developmental glaucoma.

Authors

Keiichiro Iwao, Masaru Inatani, Yoshihiro Matsumoto, Minako Ogata-Iwao, Yuji Takihara, Fumitoshi Irie, Yu Yamaguchi, Satoshi Okinami, Hidenobu Tanihara

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Figure 3

HS deficiency causes Peters-like anomaly.

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HS deficiency causes Peters-like anomaly.
(A and B) Thionin staining of ...
(A and B) Thionin staining of the eyes of Wnt1-CreExt1flox/flox and control embryos during embryonic development. At E15.5 and E18.5, Wnt1-CreExt1flox/flox embryos exhibited abnormal thinning of the central cornea (arrows) and dysgenesis of the iridocorneal angle (open arrowheads). While the control eye shows lid closure (black arrowheads in B), the mutant embryo lacked eyelids. Boxed regions in B indicate the areas shown at higher magnification in A. (C) Impaired ocular growth in Wnt1-CreExt1flox/flox embryos. The central cornea thickness and the anterior chamber depth in the mutant embryos were significantly smaller, as compared with the control eyes. However, the lens thickness was not affected in the eyes of mutants. (D) Van Gieson staining revealed collagen accumulation in the control corneal stroma. In contrast, Wnt1-CreExt1flox/flox embryos lacked collagen matrix. (E) Immunohistochemistry using anti–ZO-1 antibody exhibited a defect of the endothelial layer in the mutant cornea. (F) Fate mapping for neural crest cells. Cre-positive neural crest cells had already migrated to the periocular region as early as E11.5, while the neural crest cells remained distributed at E18.5. Data represent mean ± SEM. *P < 0.05, **P < 0.01, Student’s t test (n = 6). c, cornea; ICA, iridocorneal angle; KO, Wnt1-CreExt1flox/flox. Scale bar: 50 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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