Genetic Analysis of Visual-System Development

视觉系统发育的遗传分析

• 批准号: 6560672
• 负责人: HERWIG BAIER
• 金额: $ 30.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6560672
• 关键词: biological signal transduction; cell differentiation; developmental neurobiology; fibroblast growth factor; gene expression; genetically modified animals; green fluorescent proteins; immunocytochemistry; in situ hybridization; neurogenesis; retinal ganglion; site directed mutagenesis; transcription factor; visual pathways; zebrafish

DESCRIPTION (provided by applicant): The molecular mechanisms underlying visual-system development are only beginning to be understood. The long-term objectives of this work are the identification and characterization of molecules that govern the differentiation of neuronal classes in the visual pathway. The vertebrate retina is composed of over 50 neuronal cell types that fall into 6 major classes. This proposal focuses on one prominent class, the retinal ganglion cells, which connect the eye to the brain. The current model of retinal neurogenesis proposes that cell classes are generated during development from multipotential progenitors in an invariant temporal order. Ganglion cells are always born first; they emerge from a sheet of undifferentiated progenitor cells in the form of a wave that sweeps across the embryonic eye. In this grant, we will use a genetic approach in zebrafish, to investigate the molecular interactions that underlie the ganglion-cell differentiation wave. The recently discovered transcription factor Ath5 is of central importance, since its mutation in the zebrafish mutant lakritz eliminates all ganglion cells. We will test its interactions with the factors Shh, Twhh, Fgfl, and Brn3c, which have been implicated in ganglion-cell genesis. We will further ask whether Ath5 is also involved in subsequent steps of differentiation of retinal ganglion cells. Finally, we will attempt to discover novel genes in a mutagenesis screen taking advantage of a transgenic zebrafish line that expresses GFP in ganglion cells. These studies will establish a genetic pathway of factors involved in determination, differentiation, and diversification of retinal ganglion cells. Health-relatedness. This approach may lead a way to isolating genes involved in diseases of the human retina, such as glaucoma and optic-nerve hypoplasia, for which there are currently no cures

描述（由申请人提供）：视觉系统发育的分子机制才刚刚开始被理解。这项工作的长期目标是识别和表征控制视觉通路中神经元类别分化的分子。脊椎动物视网膜由 50 多种神经元细胞类型组成，分为 6 个主要类别。该提案重点关注一个重要的类别，即连接眼睛和大脑的视网膜神经节细胞。目前的视网膜神经发生模型提出，细胞类别是在多能祖细胞发育过程中以不变的时间顺序产生的。神经节细胞总是最先诞生的；它们以波的形式从一片未分化的祖细胞中出现，扫过胚胎的眼睛。在这笔资助中，我们将在斑马鱼中使用遗传方法来研究神经节细胞分化波背后的分子相互作用。最近发现的转录因子 Ath5 至关重要，因为它在斑马鱼突变体 lakritz 中的突变消除了所有神经节细胞。我们将测试它与 Shh、Twhh、Fgfl 和 Brn3c 因子的相互作用，这些因子与神经节细胞的发生有关。我们将进一步询问Ath5是否也参与视网膜神经节细胞分化的后续步骤。最后，我们将尝试利用在神经节细胞中表达 GFP 的转基因斑马鱼系，在诱变筛选中发现新基因。这些研究将建立参与视网膜神经节细胞的决定、分化和多样化的因素的遗传途径。健康相关性。这种方法可能会开辟一种方法来分离与人类视网膜疾病有关的基因，例如青光眼和视神经发育不全，而目前这些疾病还没有治愈方法