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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 6

Disturbed TGF-β2–stimulated proliferation of HS-deficient neural crest cells.

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Disturbed TGF-β2–stimulated proliferation of HS-deficient neural crest c...
(A) Immunostaining with anti-HS and anti-Cre recombinase antibodies indicated that there were Cre-transfected periocular neural crest cells with Ext1flox/flox alleles that expressed Cre recombinase while having lost HS. (B and C) BrdU proliferation assay. While the periocular neural crest cells showed TGF-β2–dependent BrdU incorporation (orange-colored cells), the HS-deficient neural crest cells had a low rate of BrdU-positive cells. There was a statistical significance found for the TGF-β2–dependent proliferation between the HS-positive and HS-deficient cells. (D) Western blot for Smad2 and phosphorylated Smad2 (p-Smad2) was analyzed in the cultured cells. While TGF-β2 enhanced the phosphorylation of Smad2, there was no phosphorylation of Smad2 in the HS-deficient neural crest cells, even after TGF-β2 stimulation. (E and F) BrdU proliferation assay in cocultures of HS-positive and HS-deficient cells. Since the HS, BrdU, and nucleus were labeled by FITC (green), Alexa Fluor 568 (red), and Hoechst 33258 (blue), respectively, the BrdU-positive cells exhibit a white-colored nucleus (white arrows) in HS-positive cells, while they have a magenta-colored nucleus in HS-deficient cells. A significant reduction of the BrdU-positive cells was seen in the HS-deficient cells (yellow arrows). (F) The comparison of the percentage of BrdU-positive cells between HS-positive and HS-negative cells in coculture. Data represent mean ± SEM. *P < 0.01, Student’s t test (n = 9). Original magnification, ×10 (A, B, and E).

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