Previously, we showed that transcription factor activating protein 2-beta (AP-2β) deletion from the periocular mesenchyme (POM)-derived neural crest cells (NCCs) using Wnt1Cre (AP-2β NCC knockouts/AP-2β NCC KOs) resulted in anterior segment abnormalities and increased intraocular pressure (IOP). The present study investigated the role of AP-2β in development of structures of the conventional pathway including the trabecular meshwork and Schlemm’s canal, and the unconventional pathway including the ciliary muscle. Studies using NCC KOs revealed that the embryonic POM migrated appropriately, but a significant reduction in postnatal POM cell proliferation in the angle was observed, accompanied by reduced expression of trabecular meshwork and Schlemm's canal markers when compared to controls, which likely contributed to the elevated IOP in NCC KOs. However, since Wnt1Cre was expressed in multiple NCC derivatives, AP-2β was deleted specifically from the developing trabecular meshwork region (TMR) using Mgp-Cre knock-in (Mgp-Cre.KI) mice. Although migration of the POM giving rise to the trabecular meshwork was not affected, peripheral anterior synechia (PAS), a decrease in expression of trabecular meshwork and Schlemm’s canal markers, and significantly increased IOP was observed in TMR KOs compared to controls, paired with loss of retinal ganglion cells (RGCs), and reduced retinal thickness and function. However, treatment with latanoprost, a prostaglandin analog that increases outflow through the unconventional pathway, significantly reduced elevated IOP in TMR KOs. Overall, the results suggest that AP-2β plays a cell-autonomous role in trabecular meshwork development and a non-cell-autonomous role in Schlemm’s canal development, while also playing an indirect role in unconventional pathway function, and thus, is important for IOP homeostasis. Moreover, the AP-2β NCC KO and AP-2β TMR KO may serve as models of primary angle closure glaucoma that can be used to test IOP-lowering drugs, molecular targets and neuroprotective strategies to develop treatments for human glaucoma. / Thesis / Doctor of Philosophy (PhD) / Glaucoma is the leading cause of irreversible blindness worldwide. Primary angle closure glaucoma is one type of glaucoma resulting from abnormalities in structures that allow aqueous humour found in the front of the eye from exiting the eye through two major routes, including the conventional and unconventional pathways. Defects in these structures lead to increased intraocular pressure (IOP) that damages specialized cells important for vision. This project examines the role of transcription factor activating protein 2-beta (AP-2β) in development of structures responsible for IOP balance. Data from the current study showed that AP-2β is required for formation of the structures of the conventional pathway, but does not directly affect development of unconventional pathway structures. The two AP-2β deletion mutants used here can model human primary angle closure glaucoma to test the effect of various drugs and cell protection strategies aimed at treating glaucoma.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/26988 |
| Date | January 2021 |
| Creators | Akula, Monica |
| Contributors | West-Mays, Judith |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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