Summary The leading cause of blindness in Americans over the age of 60 is glaucoma. One risk factor for glaucoma is central corneal thickness. The thinner the cornea, the greater the risk of developing glaucoma. Recently, we have identified a transcription factor, POU6F2, that modulates central corneal thickness in the mouse and that is a risk factor for human glaucoma. The Pou6f2 knockout mouse has a thinner cornea than its wild-type littermates, while there is no apparent change in intraocular pressure. We propose that POU6F2 is expressed in novel subclasses of retinal ganglion cells (RGCs) that are sensitive to glaucomatous injury. Premise: Our four findings lead us to hypothesize that POU6F2 is in a transcriptional cascade responsible for the susceptibility and early death of a novel collection of ON-OFF directionally selective RGC subtypes. To test this hypothesis, we will focus on the role of POU6F2 in the response of RGCs in models of experimentally-induced and naturally- occurring glaucoma. The proposed experiments will uncover the POU6F2 molecular cascade that induces glaucomatous damage. We will relate our findings in the mouse to the human, through a collaboration with Dr. Janey Wiggs and the NEIGHBORHOOD consortium, interrogating the NEIGHBORHOOD meta-dataset to define molecular pathway associated with POU6F2 targets. We will determine if any of these downstream targets and their associated pathways represent factors for glaucoma risk. This basic understanding of the molecular interactions of POU6F2 will inform the rational design of strategies to improve detection of and therapy for glaucoma.