Loss of Class III Phosphoinositide 3-Kinase Vps34 Results in Cone Degeneration

SIMPLE SUMMARY: Cone photoreceptors are the class of neurons in the retina that support daylight and color vision. In humans and rodents, the cone photoreceptors constitute a small percentage of total retinal photoreceptors; in some retinal diseases, these cells malfunction over time and cease to work, and eventually die. Class III phosphoinositide 3-kinase, also known as vacuole protein sorting 34 (Vps34), generates phosphoinositide 3-phosphate (PI(3)P), a lipid molecule that transmits information inside of the cell. PI(3)P plays an essential role in removing injured cells, a process called autophagy, which maintains a healthy environment, as well as in protein trafficking inside of the cell. Furthermore, PI(3)P can act as a bridging molecule for proteins to bind to each other. We eliminated the class III phosphoinositide 3-kinase in mouse cones, which resulted in the loss of visual function and death of cone cells. Our studies suggest that PI(3)P generated by class III phosphoinositide 3-kinase is essential for cone photoreceptor function and survival. ABSTRACT: The major pathway for the production of the low-abundance membrane lipid phosphatidylinositol 3-phosphate (PI(3)P) synthesis is catalyzed by class III phosphoinositide 3-kinase (PI3K) Vps34. The absence of Vps34 was previously found to disrupt autophagy and other membrane-trafficking pathways in some sensory neurons, but the roles of phosphatidylinositol 3-phosphate and Vps34 in cone photoreceptor cells have not previously been explored. We found that the deletion of Vps34 in neighboring rods in mouse retina did not disrupt cone function up to 8 weeks after birth, despite diminished rod function. Immunoblotting and lipid analysis of cones isolated from the cone-dominant retinas of the neural retina leucine zipper gene knockout mice revealed that both PI(3)P and Vps34 protein are present in mouse cones. To determine whether Vps34 and PI(3)P are important for cone function, we conditionally deleted Vps34 in cone photoreceptor cells of the mouse retina. Overall retinal morphology and rod function appeared to be unaffected. However, the loss of Vps34 in cones resulted in the loss of structure and function. There was a substantial reduction throughout the retina in the number of cones staining for M-opsin, S-opsin, cone arrestin, and peanut agglutinin, revealing degeneration of cones. These studies indicate that class III PI3K, and presumably PI(3)P, play essential roles in cone photoreceptor cell function and survival.