The role of microRNA in the cell fate specification of photoreceptors

microRNA在光感受器细胞命运规范中的作用

• 批准号: 9107619
• 负责人: DAVID B MORTON
• 金额: $ 23.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107619
• 关键词: Adult; Afferent Neurons; Binding; Biogenesis; CRX protein; Cell division; Cells; Cone; Cues; Data; Degenerative Disorder; Development; Disease; Drosophila eye; Drosophila genus; Drosophila melanogaster; Ensure; Eye; Future; Gene Expression; Generations; Genes; Genetic; Goals; Hour; Human; Individual; Investigation; Knowledge; Lead; Leucine Zippers; Light; Link; Mammals; Mediating; MicroRNAs; Mitotic; Modeling; Molecular; Molecular Genetics; Morphology; Mutation; Nervous system structure; Neural Retina; Neurons; Opsin; Pathway interactions; Photoreceptors; Pigments; Play; Post-Transcriptional Regulation; Process; Proteins; Regulation; Regulator Genes; Reporting; Repression; Retina; Retinal; Retinal Cone; Retinal Degeneration; Retinitis Pigmentosa; Rhodopsin; Role; Scallop; Signal Pathway; Signal Transduction; Specific qualifier value; Syndrome; System; Testing; Time; Tissues; Untranslated Regions; bZIP Domain; base; cell fate specification; cell injury; cell type; design; developmental disease; fly; gene function; molecular pathology; novel; organ growth; overexpression; programs; protein expression; public health relevance; retinal rods; trafficking; transcription factor

 DESCRIPTION (provided by applicant): Generation of distinct neuronal subtypes is a prerequisite for formation of a functional nervous system. For example, generation of rods and the three subtypes of cone cells in the mammalian retina are essential for receiving environmental light cues. Abnormal photoreceptor cell fate specification is frequently associated with retinal congenital and degenerative diseases and studies in the last decades have identified numerous photoreceptor cell fate determinant genes. Mutations in these genes are often linked to retinal developmental disorders and diseases. However, the molecular mechanisms underlying how these genes specify distinct photoreceptor subtypes and how they are regulated remains incomplete. This proposal is focused on understanding the regulatory mechanisms that determine a mutually exclusive binary choice between two photoreceptor cell fates using the fruit fly, Drosophila melanogaster. The conservation of the regulatory genes determining cell fate of photoreceptors between mammals and flies is remarkable. In mammals the choice between rods or cones is determined by the interplay between the cone-rod homeobox (Crx) protein and the neural retina-specific leucine zipper (NRL) protein. The Drosophila orthologues of these genes, Otd and Tj, regulate the choice of a specific photoreceptor between expressing one of two photo-pigments, rhodopsin 5 (Rh5) or rhodopsin 6 (Rh6). Our recent studies revealed that in Drosophila photoreceptors, the function of these genes is regulated by the Hippo signaling pathway, a signaling system that has also been shown to be highly conserved in regulating cell division and organ growth in both mammals and flies. Our preliminary studies have strongly suggested that multiple microRNAs are also involved in this photoreceptor subtype specification. microRNAs have been illustrated playing important regulatory roles in various developmental and disease processes, but their role in photoreceptor subtype fate specification is still unknown. In this proposal, we will use genetic and molecular approaches to elucidate how these microRNAs specify photoreceptor subtype fates by regulating conserved fate determinant genes and the photo-pigment genes. In addition, we will investigate how the biogenesis of these microRNAs is regulated by the newly identified Hippo signaling pathway. These studies will provide novel molecular mechanisms underlying neuronal subtype fate specification that will help understand the basis for a variety of developmental disorders and potentially aid in the design of strategies for directed differentiation of human pluripotent cells into specific cell types to replace the damaged cells in degenerative neuronal tissues.

 描述（应用程序提供）：不同的神经元亚型的产生是形成功能性神经系统的先决条件。例如，哺乳动物视网膜中锥细胞的杆和三个亚型的产生对于接收环境光提示至关重要。异常的感光细胞脂肪规格通常与视网膜先天性和退化性疾病有关，并且在过去几十年中的研究已经确定了许多光感受器细胞脂肪确定的基因。这些基因的突变通常与视网膜发育障碍和疾病有关。但是，这些基因如何指定不同的光感受器亚型及其调节方式的分子机制仍然不完整。该提案的重点是理解使用果蝇果蝇果蝇（Drosophila Melanogaster）在两个感光细胞命运之间互斥二元选择的调节机制。在哺乳动物和苍蝇之间确定光感受器细胞命运的调节基因的保护是显着的。在哺乳动物中，棒或锥之间的选择是由锥体杆型（CRX）蛋白与神经视网膜特异性亮氨酸拉链（NRL）蛋白之间的相互作用确定的。这些基因OTD和TJ的果蝇直系同源物调节表达两种光合物之一，即Rhodopsin 5（Rh5）或Rhodopsin 6（Rh6）之间的特定光感受器的选择。我们最近的研究表明，在果蝇感光体中，这些基因的功能受HIPPO信号通路的调节，河马信号通路是一种信号系统，该信号系统也被证明在调节细胞分裂和哺乳动物和蝇中的器官生长中高度构成。我们的初步研究强烈表明，多个microRNA也参与了该光感受器亚型规范。已经说明了MicroRNA在各种发育和疾病过程中扮演重要的调节作用，但是它们在光感受器亚型命运规范中的作用仍然未知。在此提案中，我们将使用遗传和分子方法来阐明这些microRNA如何通过控制构成的命运确定的基因和照片分配基因来指定光感受器亚型的命运。此外，我们将研究这些microRNA的生物发生如何受到新鉴定的河马信号通路的调节。这些研究将为神经元亚型命运规范提供基础的新分子机制，这将有助于理解各种发育障碍的基础，并有可能帮助设计将人类多能细胞转化为特定细胞类型的策略，以将损伤细胞替代退化性神经元组织中的受损细胞。