Genetic analysis of cone photoreceptor determination

描述(申请人提供)：视网膜光感受器是高度专业化的神经元，具有独特的、与光子检测和神经信号转导相关的分化特征。单个光感受器亚型的分布、间距和光谱一致性是影响视觉功能许多特性的重要参数，包括对弱光的敏感性、视力、色觉等。大多数脊椎动物，包括斑马鱼，都有多种光谱类别的锥形和杆状光感。然而，光感受器决定和细胞命运选择的分子控制，特别是调节锥体光谱类别选择的机制，还知之甚少。在一定程度上，这是因为典型的模型系统(啮齿动物)的视网膜以杆状为主。相比之下，硬骨鱼有丰富的锥体光感受器，斑马鱼已经成为发现发育调控基因的前向遗传学研究的有力模型。建议的突变筛选的目的是表征斑马鱼突变体的特征，这些突变体选择性地扰乱发育中的视网膜视锥感光细胞的细胞命运决定，并鉴定相关基因。 斑马鱼视网膜中的视锥感光器包括四种光谱类型，每种类型都表达一种特定的视蛋白基因，该基因产生一种视觉色素，其最大吸收波长分别对应于红、绿、蓝或紫外线。斑马鱼视网膜中的锥体形成了精确的马赛克图案，一排排红色和绿色的双锥体与一排排蓝色和紫外线的单锥体交替排列，叠加在重复的镜像对称的固有图案上。视锥马赛克图案产生于从视柄到视网膜边缘横扫假定的光感受器层的曲线分化波。控制锥光感受器细胞命运以产生这种高度有序的空间阵列的机制尚不清楚。视锥镶嵌图案的空间和时间组织的精确度使其成为识别扰乱视锥感光细胞组织和细胞类型规范的基因的理想模型系统。 研究视锥细胞光感受器细胞命运的决定和模式的基本原理是，导致神经元指定的基本发育过程的改变被认为是导致人类大脑和视网膜的一些先天性畸形的原因，这些畸形损害了神经元的功能，并可能导致死亡、发病率、身体或智力残疾。发现斑马鱼视网膜中形成视锥感光细胞阵列的分子机制将有助于更好地理解调控视网膜细胞命运选择和调节视觉行为的因素。

DESCRIPTION (provided by applicant): Retinal photoreceptors are highly specialized neurons with unique, differentiated features associated with detection of photons and transduction of neural signals. The distribution, spacing and spectral identity of individual photoreceptor subtypes is an important parameter that influences many properties of visual function, including sensitivity to low levels of light, visual acuity, color vision, etc. Most vertebrates, including zebrafish, have multiple spectral classes of cone photoreceptors as well as rod photoreceptors. However, the molecular control of photoreceptor determination and cell fate choice, especially the mechanisms that regulate choice of cone spectral classes, are poorly understood. In part, this is because the typical model system (rodents) have rod-dominated retinas. In contrast, teleost fish have abundant cone photoreceptors, and the zebrafish has emerged as a powerful model for forward genetic studies to discover developmental regulatory genes. The objective of the proposed mutagenesis screen is to characterize zebrafish mutants that selectively disrupt cell fate determination of cone photoreceptors in the developing retina and to identify the genes involved. The cone photoreceptors in zebrafish retina include four spectral types, each of which expresses a specific opsin gene that produces a visual pigment with a maximum absorption at wavelengths corresponding to red, green, blue or ultraviolet, respectively. The cones in the zebrafish retina form a precise mosaic pattern such that rows of red and green double cones alternate with rows of blue and ultraviolet single cones, superimposed on an intrinsic pattern of reiterative, mirror-image symmetry. The cone mosaic pattern is generated in a curvilinear wave of differentiation that sweeps across the presumptive photoreceptor layer from optic stalk to retinal margin. The mechanisms that control cell fate determination of cone photoreceptors to produce this highly ordered spatial array are not known. The precision of the spatial and temporal organization of the cone mosaic pattern makes this an ideal model system in which to identify genes that perturb the organization and cell type specification of cone photoreceptors. The rationale for studying cone photoreceptor cell fate determination and patterning is that alterations in the fundamental developmental processes that lead to neuronal specification are thought to be responsible for a number of congenital malformations of the human brain and retina, which impair neuronal function and can result in mortality, morbidity, physical or mental disabilities. Discovering the molecular mechanisms that pattern the cone photoreceptor array in the zebrafish retina will lead to a better understanding of the factors that regulate choice of retinal cell fate and mediate visual behaviors.