| dc.description.abstract | The retinal pigment epithelium (RPE) is a monolayer of pigmented cuboidal cells that separates the retina from the choroid and is crucial for vision. Defective RPE function and RPE atrophy can often cause age-related macular degeneration (AMD), one of the leading causes of blindness in the elderly population globally.
Although the healthy adult RPE maintains many properties of classic barrier epithelia, it does not retain the capacity to undergo cell turnover and self-renewal. Instead, the RPE supports tissue homeostasis via long-term survival. However, due to the growth of the eye and cell death throughout aging, RPE cell density often decreases over time. Furthermore, as the RPE ages, it undergoes functional and structural changes that often lead to RPE dysfunction and atrophy. There is evidence that the RPE has potential to self-repair and proliferate, but the molecular mechanisms driving this process are poorly understood. The Hippo signaling pathway plays an important role in the regulation of cell proliferation, differentiation, apoptosis, and tissue regeneration. This dissertation investigates the role of the Hippo signaling pathway in regulating RPE proliferation, repair, and injury response.
We investigated how Neurofibromin 2 (NF2) a known upstream regulator of the mammalian Hippo pathway, regulates RPE proliferation and optic fissure closure during eye development. Here, I demonstrate that NF2 promotes nuclear YAP localization in the ventral RPE, and results in overproduction of dorsal RPE cells and ectopic proliferation in the ventral RPE. I also interrogated whether I could use this approach of genetically disrupting Nf2 in the adult RPE to promote RPE repair and proliferation after injury. I demonstrate promising preliminary results that the RPE can proliferate after injury; however due to confounding challenges, I determined that NF2 is not a robust regulator of RPE proliferation in the adult tissue. However, the Hippo pathway is still a promising approach to investigate endogenous proliferation, as expression of YAP5SA results in proliferation in the RPE and decreased injury. Last, it has been previously shown that YAP is important for RPE fate and maintenance but can also play a role in epithelial-mesenchymal transition (EMT) of other tissues. In vivo, loss of Yap in the RPE results in loss of RPE characteristics and indication of EMT, but YAP is required for RPE EMT to occur in vitro. Thus, I interrogated whether YAP is critical for regulating RPE injury response and EMT after sodium iodate in vivo. Here, I determine that YAP appears to be important for promoting EMT in the RPE after injury, as haploinsuffiency and loss of Yap results in a dampened injury response. | |
