Melanopsin-dependent light-evoked development of rod photoreceptors

视杆细胞光感受器黑视蛋白依赖性光诱发发育

• 批准号: 10735293
• 负责人: Richard A. Lang
• 金额: $ 40.13万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735293
• 关键词: Adult; Amaze; Apoptosis; Birth; Blood Vessels; Cell Death; Cessation of life; Cone; Data; Dendrites; Development; Developmental Process; Environment; Etiology; Eye; Eye Development; Eye diseases; G alpha q Protein; GTP-Binding Proteins; Glutamate Receptor; Glutamates; Health; Human; Label; Light; Link; Mediating; Mus; Neonatal; Neuromodulator; Pathway interactions; Pattern; Perinatal; Photoreceptors; Process; Public Health; Recording of previous events; Retina; Retinal Ganglion Cells; Retinal Photoreceptors; Rod; Sensory; Structure; Study models; Systems Development; Testing; Time; Traction; Visual; Visual System; Work; dark rearing; design; experience; genetic approach; glutamatergic signaling; interest; intimate behavior; loss of function; melanopsin; novel; organ growth; postnatal; precursor cell; prevent; progenitor; response; retinal neuron; retinal rods; sensor; single cell analysis; single cell sequencing; vision development

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.

一段时间以来，人们已经知道视觉系统的发展可以是一种适应性的 光线照射或视觉体验改变最终结构的过程。 提议研究通过 OPN4 进行光感受的发育途径 本质光敏视网膜神经节细胞（ipRGC）调节视杆细胞感光器 初步数据表明，光和 OPN4 调节视杆细胞前体细胞的死亡。 成年小鼠的新生视网膜和视杆细胞数量是由神经调节剂谷氨酸介导的。 我们认为 ipRGC 外层视网膜树突 (ORD) 将谷氨酸输送到外层视网膜， ORD 是 ipRGC 所特有的，并且是短暂的，仅在第一个过程中存在。 出生后一周，单细胞测序数据显示谷氨酸受体 Grik3 被表达。 出生后第一周内短暂存在于视杆细胞前体中，因此是调解的良好候选者 这些数据表明了围产期光传感的中心假设。 ipRGCs 通过谷氨酸诱导的前体细胞死亡来调节视杆细胞的数量。 我们提出了三个目标，旨在定义所提出的自适应机制的机制 我们将定义 ORD 的发育时间进程并评估其标记。 谷氨酸功能（目标 1），评估 light-OPN4-Gαq-rod 细胞中提出的关系 死亡途径（目标 2），并评估 ipRGC ORD 的谷氨酸递送和杆的反应 早期发育光感应调节数量的发现（目标 3）。 杆状光感受器的研究是出乎意料的并且引起了广泛的兴趣，因为它代表了一种新颖的 机制并对人眼发育具有影响。

项目成果

A new Opn4cre recombinase mouse line to target intrinsically photosensitive retinal ganglion cells (ipRGCs).

一种新的 Opn4cre 重组酶小鼠系，可靶向内在光敏视网膜神经节细胞 (ipRGC)。

• 发表时间: 2024-04-20
• 作者: Dyer, Brannen;Yu, Sue O;Lane Brown, R;Lang, Richard A;D'Souza, Shane P
• 通讯作者: D'Souza, Shane P