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

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 5

HS deficiency leads to the inactivation of TGF-β2 signaling and downregulation of the transcription factors Foxc1 and Pitx2.

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HS deficiency leads to the inactivation of TGF-β2 signaling and downregu...
A thin cornea (black arrows in A) and iridocorneal dysgenesis (black arrowheads in B) were observed in the mutant embryos that lacked the gene for TGF-β2 (E18.5). (C) Binding assay indicated that HS had an affinity for TGF-β2 but not for EGF. Immunohistochemical staining of TGF-β2 (D and I), Smad2 (E and J), and phosphorylated Smad2 (F and K) in the iridocorneal angle of the E13.5 embryo, and Foxc1 (G and L) and Pitx2 (H and M) in the anterior eye segment of the E15.5 embryo. A disturbance was noted for the phosphorylation of Smad2 in the periocular mesenchyme (dotted lines in F and K) in the Wnt1-CreExt1flox/flox embryos. In the eyes of mutants, the expression of Foxc1 was substantially reduced in the corneal endothelial layer (white arrows) and in the iridocorneal angle (open arrows), while Pitx2 expression was hardly detected in the corneal stroma or endothelium. en, corneal endothelium; epi, corneal epithelium; str, corneal stroma; *, presumptive ciliary body. Scale bar: 20 μm.