Genetic analysis of cone photoreceptor determination

描述（由申请人提供）：视网膜光感受器是高度特化的神经元，具有独特的、不同的特征，与光子检测和神经信号转导有关。单个光感受器亚型的分布、间距和光谱特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、视敏度、色觉等。大多数脊椎动物，包括斑马鱼，都有多种光谱类型的锥状光感受器和杆状光感受器。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，尚不清楚。在某种程度上，这是因为典型的模型系统（啮齿动物）有杆状视网膜。相比之下，硬骨鱼有丰富的视锥光感受器，斑马鱼已经成为一个强大的模型，为未来的遗传研究发现发育调节基因。提出的诱变筛选的目的是表征斑马鱼突变体，这些突变体选择性地破坏发育中的视网膜中视锥光感受器的细胞命运决定，并识别相关基因。

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.