Anterior segment dysgenesis (ASD) is a developmental anomaly of the eye that can involve multiple tissues including the cornea, iris, lens, ciliary body and ocular drainage structures including the trabecular meshwork (TM) and Schlemm's canal. As a result, ASD is associated with an increased risk of glaucoma and corneal opacities. In fact, glaucoma will arise in 50% of patients with ASD due to disruption in aqueous humour drainage, which leads to an elevation in intraocular pressure (IOP). Malformation of structures in the anterior segment of the eye is thought to occur due to a defect in the differentiation and migration of the periocular mesenchyme (POM), a derivative of neural crest. Although inappropriate patterning of the POM is strongly implicated in ASD, the mechanisms of POM function and/or disruption in ASD are unclear. Our laboratories have shown that activating transcription factor (AP-2) is highly expressed in the POM and POM-derived tissues of the post-natal mouse eye. Furthermore, we have found that conditional deletion of Tfap2b (the gene encoding AP-2) in the POM (using a Wnt-1 Cre driver that targets the POM of the eye) leads to a fully penetrant, angle closure glaucoma phenotype with the iris adhering to the cornea. Interestingly, our preliminary findings also show that the Wnt-1Cre/AP-2 mutant's exhibit features of glaucoma including RGC loss and increased retinal glial reactivity. In the current proposal we will continue to utilize conditional KO approaches in mice to identify the individual role(s) that the AP-2 gene plays in development of the anterior angle tissues including the TM and cornea. We will also use state-of-the-art omics level analyses to determine the patterns of normal gene expression in the anterior segment and how they are disrupted by loss of Tfap2b. Finally, we will further assess the glaucomatous changes observed in the mouse models generated to further understand the pathophysiology of closed angle glaucoma and optic neuropathy.
Glaucoma is one of the leading causes of visual disability in the United States (more than 2.7 million cases) and throughout the world (more than 60 million cases), and is a leading cause of irreversible blindness among African Americans and Hispanics. As the population ages and life expectancy increases the number of patients with glaucoma is expected to increase considerably. Anterior segment dysgenesis (ASD) is a developmental anomaly that can involve multiple tissues in the anterior segment of the eye and is associated with an increased risk of glaucoma and corneal opacities. In fact, glaucoma will arise in 50% of patients with ASD due to disruption in aqueous humour drainage, which leads to an elevation in intraocular pressure (IOP). In ASDs, malformation of structures in the anterior segment of the eye is thought to occur due to a defect in the differentiation and migration of the periocular mesenchyme (POM), a derivative of neural crest. Although inappropriate patterning of the POM is strongly implicated in ASD, the mechanisms of POM function and/or disruption in ASD are unclear. In the proposed research we will investigate the role of a novel player in anterior segment development, AP-2. Through the use of conditional KO approaches in mice we will identify the individual role(s) that the AP-2 gene plays in development of the anterior angle tissues including the TM and cornea. We will also use state-of-the-art 'omics' level analyses to determine the patterns of normal gene expression in the anterior segment and how they are disrupted by loss of AP-2. Finally, we will further assess the glaucomatous changes observed in the mouse models generated to further understand the pathophysiology of closed angle glaucoma and optic neuropathy.
| Hicks, Emily Anne; Zaveri, Mizna; Deschamps, Paula A et al. (2018) Conditional Deletion of AP-2? and AP-2? in the Developing Murine Retina Leads to Altered Amacrine Cell Mosaics and Disrupted Visual Function. Invest Ophthalmol Vis Sci 59:2229-2239 |
| Martino, Vanessa B; Sabljic, Thomas; Deschamps, Paula et al. (2016) Conditional deletion of AP-2? in mouse cranial neural crest results in anterior segment dysgenesis and early-onset glaucoma. Dis Model Mech 9:849-61 |
| Chen, Lisheng; Martino, Vanessa; Dombkowski, Alan et al. (2016) AP-2? Is a Downstream Effector of PITX2 Required to Specify Endothelium and Establish Angiogenic Privilege During Corneal Development. Invest Ophthalmol Vis Sci 57:1072-81 |
| De Groef, Lies; Andries, Lien; Siwakoti, Anuja et al. (2016) Aberrant Collagen Composition of the Trabecular Meshwork Results in Reduced Aqueous Humor Drainage and Elevated IOP in MMP-9 Null Mice. Invest Ophthalmol Vis Sci 57:5984-5995 |
