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

基本信息

批准号：
9258435
负责人：
DAVID B MORTON
金额：
$ 19.25万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9258435
关键词：
3&apos Untranslated Regions 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 Genetic Transcription Goals Hour Human Individual Investigation JAM protein Knowledge Lead Leucine Zippers Light Link Mammals Mediating MicroRNAs Mitotic Modeling Molecular Morphology Mutation Nervous system structure Neural Retina Neurons Opsin Pathway interactions Photoreceptors Pigments Play Post-Transcriptional Regulation Process Proteins Pupa 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 bZIP Domain 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 transcription factor

项目摘要

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（由申请人提供）：不同神经亚型的产生是形成功能性神经系统的先决条件，例如，哺乳动物视网膜中视杆细胞和视锥细胞的三种亚型的产生对于接收异常光感受器至关重要。细胞命运规范通常与视网膜先天性和退行性疾病相关，过去几十年的研究已经发现许多感光细胞命运决定基因通常与这些基因的突变有关。然而，这些基因如何指定不同的光感受器亚型以及它们如何被调节的分子机制仍然不完整，该提案的重点是了解使用决定两种光感受器细胞命运之间相互排斥的二元选择的调节机制。果蝇，果蝇，哺乳动物和果蝇之间决定光感受器细胞命运的调节基因的保守性是显着的，在哺乳动物中，视杆细胞或视锥细胞之间的相互作用决定了它们的选择。视锥杆同源框 (Crx) 蛋白和神经视网膜特异性亮氨酸拉链 (NRL) 蛋白这些基因 Otd 和 Tj 的果蝇直系同源物调节表达两种感光色素之一视紫红质 5 之间的特定感光细胞的选择。 (Rh5) 或视紫红质 6 (Rh6) 我们最近的研究表明，在果蝇光感受器中，这些基因的功能受到调节。我们的初步研究强烈表明，多种 microRNA 也参与了这种光感受器亚型规范。已被证明在各种发育和疾病过程中发挥重要的调节作用，但它们在光感受器亚型命运规范中的作用仍然未知。在本提案中，我们将使用遗传和分子方法来阐明这些 microRNA 如何指定光感受器。此外，我们将研究新发现的 Hippo 信号通路如何调节这些 microRNA 的生物发生，这些研究将提供神经亚型命运规范的新分子机制。将有助于了解各种发育障碍的基础，并可能有助于设计将人类多能细胞定向分化为特定细胞类型以替换退行性神经组织中受损细胞的策略。