THE ROLE OF TRANSCRIPTION FACTOR AP-2β IN THE DEVELOPMENT OF OCULAR ANTERIOR SEGMENT STRUCTURES INVOLVED IN INTRAOCULAR PRESSURE HOMEOSTASIS

Abstract

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.