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，具有与光子检测和神经信号转导相关的独特、分化的特征。个体光感受器亚型的分布、间距和光谱特性是影响视觉功能的许多特性的重要参数，包括对低水平光的敏感性、视敏度、色觉等。大多数脊椎动物，包括斑马鱼，具有多个光谱类别的视锥光感受器和视杆光感受器。然而，光感受器决定和细胞命运选择的分子控制，特别是调节锥光谱类别选择的机制，知之甚少。在某种程度上，这是因为典型的模型系统（啮齿动物）具有杆主导的视网膜。相比之下，硬骨鱼有丰富的视锥细胞，斑马鱼已成为一个强大的模型，为向前遗传学研究，发现发育调控基因。拟议的诱变筛选的目的是表征斑马鱼突变体，选择性地破坏细胞的命运决定锥光感受器在视网膜发育，并确定所涉及的基因。 斑马鱼视网膜中的视锥光感受器包括四种光谱类型，每种光谱类型表达特定的视蛋白基因，所述视蛋白基因产生在分别对应于红色、绿色、蓝色或紫外线的波长处具有最大吸收的视觉色素。斑马鱼视网膜中的视锥细胞形成了一种精确的镶嵌图案，红色和绿色的双视锥细胞与蓝色和紫外线的单视锥细胞交替排列，叠加在一种内在的镜像对称图案上。视锥镶嵌模式产生于一个曲线波的分化，从视柄到视网膜边缘扫过假定的感光层。控制视锥光感受器的细胞命运决定以产生这种高度有序的空间阵列的机制尚不清楚。锥镶嵌图案的空间和时间组织的精确性使得这是一个理想的模型系统，在其中识别扰乱锥光感受器的组织和细胞类型规格的基因。 研究视锥光感受器细胞命运决定和模式化的基本原理是，导致神经元特化的基本发育过程的改变被认为是人类大脑和视网膜的许多先天性畸形的原因，这些畸形损害神经元功能并可导致死亡、发病、身体或精神残疾。发现斑马鱼视网膜中的视锥细胞阵列的分子机制，将导致更好地理解调节视网膜细胞命运选择和介导视觉行为的因素。

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.