Role of AP-2beta in Anterior Segment Development

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 DESCRIPTION (provided by applicant): 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 ß (AP-2ß) 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-2ß) 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-2ß 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-2ß 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.