Melanopsin-dependent light-evoked development of rod photoreceptors

已经知道视觉系统的发展可以是自适应的 光曝光或视觉体验改变最终结构的过程。在这里我们 建议研究通过OPN4的光接收的发育途径 固有的光敏性视网膜神经节细胞(IpRGCs)对视杆感受器的调节 生死存亡。初步数据显示，光和OPN4调节视杆前体细胞的死亡。 成年小鼠的新生视网膜和视杆细胞数。这是由神经调节剂谷氨酸调节的。 我们认为，ipRGC视网膜外树突(ORD)将谷氨酸输送到视网膜外，并 规范棒的存活期。ORD是ipRGC独有的，是暂时的，仅在第一个期间存在 出生后一周。单细胞测序数据显示谷氨酸受体Grik3表达 在出生后第一周短暂地出现在杆状前体中，因此是一个很好的介导者 这样的回应。这些数据表明，围产期光感知的中心假设是 IpRGCs通过谷氨酸诱导的前体细胞死亡来调节杆状感光细胞的数量。 我们提出了三个目标，旨在定义这种拟议的自适应机制 回应。我们将确定ODS的发展时间进程，并评估ODS的标志物 谷氨酸功能(目标1)，评估LIGHT-OPN4-GαQ-杆细胞中所提出的关系 死亡途径(目标2)，并评估ipRGC Ords的谷氨酸递送和ROD的反应 前体(目标3)。早期发育的光感知调节数量的发现 是出乎意料的，并引起了广泛的兴趣，因为它代表了一种新的 机制，并对人眼发育有影响。

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.