title: [Exploration of the molecular mechanism of ocular development and the creation of animal models for ocular diseases].
abstract: Optic nerve pathfinding is a useful model for investigating neural network formation in the central nervous system (CNS). Understanding the molecular mechanism underlying optic nerve pathfinding will lead to progress in regenerative therapy for acquired CNS damage such as glaucoma and spinal cord injury in humans. To investigate why retinal ganglion cells extend their axons toward the brain, we focused on the role of proteoglycans in optic nerve guidance. Immunohistochemical analyses showed intense upregulation in expression of proteoglycans in the inner retinal layers during eye development. We found that proteoglycans inhibited neurite outgrowth of retinal ganglion cells in culture. Subsequently, we disrupted the gene for Ext 1, an essential enzyme for glycosaminoglycan synthesis of all the heparan sulfate proteoglycans. The Ext 1 mutant mice in which Ext 1 was selectively disrupted in the CNS exhibited severe guidance errors in optic nerve and brain commissural axons when the axons crossed the midline. When the optic nerve crossed the midline at the chiasm, the vast majority of axons projected ectopically into the contralateral optic nerve. Generation of Slit2 and Ext 1 compound mutants caused disturbed activity of Slit proteins, heparin/heparan sulfate-binding chemorepulsive guidance factors. The data suggest that heparan sulfate proteoglycans in optic nerves probably modulate the activity of Slit during the optic chiasm formation. Therefore, to examine whether the interaction between heparan sulfate and heparin-binding molecules is also critical for other ocular developmental events, we selectively disrupted heparan sulfate in the neural crest cells constituent of the anterior ocular segment in mice. Heparan sulfate deficiency in neural crest cells caused anterior chamber angle dysgenesis, including corneal endothelium defects, corneal stroma hypoplasia, and iridocorneal dysgenesis. The anomalies are comparable to Peters anomaly, a type of developmental glaucoma in humans. Loss of heparan sulfate in neural crest cells disturbed TGFbeta2 signaling such as impaired TGFbeta2-dependent cell proliferation and reduced activity of TGFbeta2-downstream molecules. Furthermore, impaired interaction between heparan sulfate and TGFbeta2 caused developmental glaucoma, which was manifested as elevated intraocular pressure caused by iridocorneal angle dysgenesis. These developmental animal models revealed that heparan sulfate proteoglycans have an essential role in regulation of heparin-binding molecules in vivo.
authors.affiliation: Department of Ophthalmology and Visual Science, Kumamoto University Graduate School of Medical Sciences, Japan. inatani@kumamoto-u.ac.jp
authors.forename: Masaru
authors.initials: M
authors.lastname: Inatani
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005128:Eye Diseases; D019812:Heparan Sulfate Proteoglycans / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009900:Optic Nerve / Q000254:growth & development*; D011509:Proteoglycans / Q000502:physiology; D051381:Rats
chemical_list: D019812:Heparan Sulfate Proteoglycans; D011509:Proteoglycans