Melanopsin-dependent light-evoked development of rod photoreceptors

It has been known for some time that development of the visual system can be an adaptive process in which light exposure or visual experience modifies the final structure. Here we propose to investigate a developmental pathway in which photoreception via OPN4 in intrinsically photosensitive retinal ganglion cells (ipRGCs) regulates rod photoreceptor survival. Preliminary data show that light and OPN4 regulate rod precursor cell death in the neonatal retina and rod number in adult mice. This is mediated by the neuromodulator glutamate. We suggest that ipRGC outer retinal dendrites (ORDs) deliver glutamate to the outer retina and regulate rod survival. ORDs are unique to ipRGCs and are transient, existing only during the first week after birth. Single cell sequencing data reveal that the glutamate receptor Grik3 is expressed in rod precursors transiently in the first week after birth and is thus a good candidate to mediate this response. These data suggest the Central Hypothesis that Perinatal light sensing by ipRGCs regulates rod photoreceptor number via glutamate-induced precursor cell death. We propose three Aims designed to define the mechanisms underlying this proposed adaptive response. We will define the developmental time-course of ORDs and assess markers of glutamate function (Aim 1), assess the proposed relationships in the light-OPN4-Gαq-rod cell death pathway (Aim 2), and assess glutamate delivery by ipRGC ORDs and the response of rod precursors (Aim 3). The finding that early developmental light sensing regulates the number of rod photoreceptors is unexpected and of broad interest because it represents a novel mechanism and has implications for human eye development.