PROJECT SUMMARY Vision begins when light detecting photoreceptors in the outer retina sense and respond to visual input and relay this information to interneurons. Both the development of these connections and their long-term integrity must be precisely regulated in space and time to ensure visual information is correctly relayed. Understanding the mechanisms that coordinate these events is central to understanding the basis of many visual diseases. We have identified that the serine-threonine kinase LKB1 is differentially required for the emergence and long- term fidelity of the outer retina. Our preliminary evidence suggests that deletion of LKB1 during development inhibits outer retina synaptic formation, while deletion in adulthood causes premature synaptic decline. We are therefore extremely interested to understand how LKB1 orchestrates these distinct processes at both the cellular and molecular level. Our preliminary evidence suggests that the cells and signaling pathways that initiate and regulate these events are independent. Adults require LKB1 signaling in rods to ensure the organization of their synapses, while development of the outer retina requires LKB1 driven extension of cone axons. Moreover, LKB1 signals through district pathways to mediate these events: in adults LKB1 controls synaptic fidelity through the AMP activated kinase AMKP, while LKB1 functions independently of AMPK in development. Our first Aim will determine the precise cellular requirement for LKB1 in the outer retina during development and adulthood using cell-specific knockout mice, live imaging, and single cell reconstruction. We will also interrogate the impact of outer retina defects on the molecular organization the synapses that reside there using 3D nanoscopic imaging techniques. Our second aim will determine the mechanism by which LKB1 functions using genetic analyses of LKB1-kinase pathways and cell-specific transcriptional approaches. Finally, we will test whether manipulating AMPK or other targets can prevent or reverse visual decline. These studies will lead to the identification of novel molecular pathways for manipulating retina circuits that may ultimately be useful for repairing them.

NARRATIVE Defects in outer retina neurons are a significant cause of visual decline. We have identified a new gene, LKB1, that is differentially required in development and in adults for organizating neurons in the outer retina and ensuring that they connect properly. We believe that understanding the molecular underpinnings of visual circuit integrity in the outer retina will open new theraputic avenues for preventing or perhaps reversing vision loss.