Genetics of the photoreceptor cell specification

感光细胞规格的遗传学

• 批准号: 7810018
• 负责人: Karen Alvarez-Delfin
• 金额: $ 3.24万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7810018
• 关键词: Address; Adult; Affect; Alleles; Biological Assay; Blindness; Cells; Color Visions; Cultured Cells; Defect; Developed Countries; Development; Disease; Embryo; Exhibits; Eye diseases; Family; Fertility; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Models; Genetic Screening; Genomics; Goals; Homeobox; Human; Image; Impairment; Inherited; Knockout Mice; Light; Maintenance; Mediating; Molecular; Morphology; Mus; Mutation Analysis; Nuclear Receptors; Pathway interactions; Pattern; Phenotype; Photoreceptors; Physiology; Reporter Genes; Retina; Retinal; Retinal Cone; Retinal Dystrophy; Retinoids; Rodent; Role; Syndrome; Testing; Therapeutic Intervention; Thyroid Gland; United States; United States National Center for Health Statistics; Vertebrate Photoreceptors; Vision; Visual system structure; Zebrafish; base; cell type; developmental genetics; human disease; legally blind; member; mutant; novel; promoter; public health relevance; receptor; research study; retinal rods; tool; transcription factor; ultraviolet

DESCRIPTION (provided by applicant): The lot-of-rods (lorp25bbtl) mutant was isolated in a genetic screen of mutagenized zebrafish for changes in rod patterning in the larval retina. lorp25bbtl mutants display an increase in the number of rods and a reduction in the number of UV cones, likely due to a cell fate change. This phenotype is the opposite of that exhibited by the Nri knockout mice, which demonstrate an increase in the number of short-wavelength- sensitive cones (S cones) and a reduced number of rods. Initial characterization of the mutant shows that lorp25bbtl is a hypomorphic allele of the transcription factor tbx2b, and acts cell-autonomously in photoreceptor fate determination. This application proposes molecular studies to uncover the specific functions of tbx2b in photoreceptor development. The following topics will be addressed: 1. Is tbx2b a direct transcriptional regulator of photoreceptor genes? To answer this question a reporter gene assay in cultured cells will be performed to evaluate transcriptional modulation by tbx2b in conjunction with other retinal transcription factors in various photoreceptor promoters. 2. Taking advantage of the UV-cone depleted phenotype in lorp25bbtl and to identify UV-cone specific genes, a microarray experiment comparing the gene expression profile of lorp25bbtl and WT adult retinas will be performed. Public Health Relevance: Heritable diseases are among the leading causes of blindness in developed countries. In the United States, an estimated 80 million people suffer potentially blinding eye disease and 1.3 million people are legally blind (National Center for Health Statistics, 1996). Given the importance of visual system diseases, the direct benefits of identifying genes in zebrafish that may be involved in human disease like photoreceptor development or retinal dystrophies are obvious. Previous characterization of the lorp25bbtl mutant suggested a genetic pathway that directly contrasts that affected in the human Enhanced-S-cone Syndrome. I believe that studying tbx2b, the gene affected in lorp25bbtl, and its role in retinal development will help to dissect the developmental pathway affected in this human syndrome and ultimately will increase our understanding of retinal development and physiology.

描述（由申请人提供）：在诱变斑马鱼的遗传筛选中分离出大量视杆细胞（lorp25bbtl）突变体，以观察幼虫视网膜中视杆细胞图案的变化。 lorp25bbtl 突变体表现出视杆细胞数量的增加和紫外线视锥细胞数量的减少，这可能是由于细胞命运的变化。这种表型与 Nri 敲除小鼠表现出的表型相反，Nri 敲除小鼠表现出短波长敏感视锥细胞（S 视锥细胞）数量增加和视杆细胞数量减少。突变体的初步表征表明 lorp25bbtl 是转录因子 tbx2b 的亚等位基因，在光感受器命运决定中细胞自主地发挥作用。该申请提出了分子研究，以揭示 tbx2b 在光感受器发育中的特定功能。将讨论以下主题： 1. tbx2b 是光感受器基因的直接转录调节因子吗？为了回答这个问题，将在培养细胞中进行报告基因测定，以评估 tbx2b 与各种光感受器启动子中的其他视网膜转录因子结合的转录调节。 2. 利用lorp25bbtl中UV锥体耗尽的表型并鉴定UV锥体特异性基因，将进行比较lorp25bbtl和WT成人视网膜的基因表达谱的微阵列实验。公共卫生相关性：遗传性疾病是发达国家失明的主要原因之一。在美国，估计有 8000 万人患有潜在致盲眼病，130 万人在法律上失明（国家卫生统计中心，1996 年）。鉴于视觉系统疾病的重要性，识别斑马鱼中可能与光感受器发育或视网膜营养不良等人类疾病有关的基因的直接好处是显而易见的。先前对 lorp25bbtl 突变体的表征表明，其遗传途径与人类增强型 S 锥体综合症的影响直接形成鲜明对比。我相信，研究 tbx2b（受 lorp25bbtl 影响的基因）及其在视网膜发育中的作用将有助于剖析受这种人类综合征影响的发育途径，并最终增加我们对视网膜发育和生理学的了解。