title: Heparan sulfate deficiency leads to Peters anomaly in mice by disturbing neural crest TGF-beta2 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-beta2 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-beta2 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-beta2 signaling. Disturbances of HS synthesis might therefore contribute to the pathology of developmental glaucoma.
authors.affiliation: Department of Ophthalmology and Visual Science, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Iwao
authors.forename: Masaru
authors.initials: M
authors.lastname: Inatani
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Minako
authors.initials: M
authors.lastname: Ogata-Iwao
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takihara
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Irie
authors.forename: Yu
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okinami
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Tanihara
mesh_terms: D000818:Animals; D000867:Anterior Chamber / Q000002:abnormalities*; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000235:genetics; D005901:Glaucoma / Q000209:etiology*; D006497:Heparan Sulfate / Q000172:deficiency / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics; D019426:Integrases / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017351:N-Acetylglucosaminyltransferases / Q000502:physiology; D009432:Neural Crest / Q000166:cytology* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics; D053781:Transforming Growth Factor beta2 / Q000502:physiology*; D051155:Wnt1 Protein / Q000502:physiology; D000097577:Homeobox Protein PITX2; D000099058:Exostosin 1
chemical_list: D051858:Forkhead Transcription Factors; D006497:Heparan Sulfate; D018398:Homeodomain Proteins; D019426:Integrases; D017351:N-Acetylglucosaminyltransferases; D014157:Transcription Factors; D053781:Transforming Growth Factor beta2; D051155:Wnt1 Protein; D000097577:Homeobox Protein PITX2; D000099058:Exostosin 1; C112890:Foxc1 protein, mouse; C495246:Wnt1 protein, mouse; C045073:Cre recombinase