EVOLUTION OF NEURODEGENERATION AND OTHER SPECIALIZATIONS IN THE VERTEBRATE VISUAL SYSTEM

脊椎动物视觉系统神经退行性和其他专业化的进化

• 批准号: RGPIN-2014-06311
• 负责人: Allison, WTed
• 金额: $ 4.44万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=588933
• 关键词: EVOLUTION; NEURODEGENERATION; OTHER; SPECIALIZATIONS; VERTEBRATE

MECHANISMS AND HISTORY OF CHORDATE EYE EVOLUTION AND REGRESSION Our recent focus is on Pacific Hagfish to understand evolution of the vertebrate eye. Other cyclostomes (lampreys) and all vertebrates share a camera-style eye, thus the Hagfish (oft-reported to lack of eyes/vision) are positioned perfectly to understand the appearance of the vertebrate eye over evolutionary time. Our study of rarely-examined young Pacific Hagfish reveals novel compelling arguments that hagfish possess almost all features of a vertebrate eye, and a pineal gland; this will codify hagfish eyes as functional, though degenerating during ontogeny (not paedomorphic), and rewrite the textbook version of early chordate eye evolution. Inspired by eye degeneration in cavefish (regressive evolution), we theorize that eyes in hagfish degenerate for adaptive reasons. We are now using adult zebrafish mutants that lack eyes (troglomorphic zebrafish!), that we developed as a model of human juvenile photoreceptor degeneration, to test ultimate hypotheses of cavefish and hagfish visual system evolution. We will answer unique questions by assessing fish that are in the very earliest stages of evolving to survive an eyeless phenotype. DEVELOPMENT and FUNCTION of CONE PHOTORECEPTOR MOSAICS – Cone photoreceptors of fishes are similar in morphology and function compared to other vertebrates, yet have a striking pattern in their distribution: The four cone classes (UV-, blue-, green- & red-sensitive) are arranged in a ‘mosaic’ similar to an elaborate checkerboard and reminiscent of Drosophila ommatidia. The development and function (and thus evolution) of this striking pattern remain mysterious, and several variants have been identified in differing fish species. Pathways identified to date by forward genetics support the hypothesis that lateral induction and differential adhesion are involved in cone mosaic formation. Such hypotheses will be analyzed in zebrafish using our world-class expertise in targeted mutagenesis, and by expression of protein variants in specific cone classes. The roles of cell-cell interactions in this system will be queried using novel transgenic zebrafish allowing conditional ablation of cone photoreceptor subtypes. REGRESSIVE EVOLUTION of UV SENSITIVITY – Most fishes have substantial visual sensitivity to ultraviolet light. This sensitivity can decrease during ontogeny, as has been indentified in salmon and trout associated with their migrations. Leading hypotheses regarding adaptive value of this loss assume decreasing function of UV sensitivity in larger animals with different visual tasks. Zebrafish have been engineered to test a novel alternate hypothesis that the disappearance of UV-sensitive cones enhances performance in some visually-mediated tasks. Zebrafish have been engineered such that photoreceptor classes can be conditionally ablated or inactivated. These fish will be assessed in electrophysiology and behavioural paradigms to evaluate visual functions including wavelength discrimination. SYNTHESIS. Going forward, I have begun to integrate these three themes under an overarching umbrella. Ask not ‘Why can fish regenerate their eyes and CNS?’ but more productively ask ‘Why have mammals lost the capacity to regenerate their eyes and CNS?’. We assume CNS regeneration is adaptive. I will apply Regressive Evolution theory to inform hypotheses on the adaptive value of losing CNS regeneration. My working hypothesis is that genes involved in stem cells/regeneration have been co-opted in mammals for new functions including synaptic plasticity, learning and memory. Experimentally manipulating these genes in adult basal vertebrates is a core of our rare ability to perform targeted mutagenesis in zebrafish.

脊索动物眼的进化和退化机制及历史 我们最近的重点是太平洋盲鳗，以了解脊椎动物眼睛的进化。 其他圆口动物（七鳃鳗）和所有脊椎动物都有一个相机式的眼睛，因此八目鳗（经常被报道缺乏眼睛/视力）被完美地定位，以了解脊椎动物眼睛在进化过程中的外观。 我们的研究很少检查年轻的太平洋盲鳗揭示了新的令人信服的论点，盲鳗拥有几乎所有的功能，脊椎动物的眼睛，和松果体;这将编纂盲鳗的眼睛功能，虽然退化在个体发育（不幼态），并重写早期脊索动物眼睛进化的教科书版本。 受到洞穴鱼类眼睛退化（回归进化）的启发，我们认为盲鳗的眼睛退化是出于适应性原因。 我们现在使用的是没有眼睛的成年斑马鱼突变体（troglomorphic斑马鱼！），我们开发了一个人类青少年感光细胞退化的模型，以测试洞穴鱼和盲鳗视觉系统进化的最终假设。我们将通过评估处于进化到无眼表型生存的最早阶段的鱼类来回答独特的问题。 视锥光感受器马赛克的发育和功能--鱼类的视锥光感受器在形态和功能上与其他脊椎动物相似，但在分布上有一个惊人的模式：四种视锥类（对紫外线、蓝色、绿色和红色敏感）排列成一个“马赛克”，类似于一个精心制作的棋盘，让人想起果蝇的小眼。这种惊人模式的发展和功能（以及进化）仍然是个谜，在不同的鱼类中已经发现了几种变体。迄今为止，通过正向遗传学确定的途径支持这样的假设，即侧诱导和差异粘附参与了球果镶嵌的形成。这些假设将使用我们在靶向诱变方面的世界级专业知识，并通过在特定锥类中表达蛋白质变体来分析斑马鱼。将使用允许视锥光感受器亚型有条件消融的新型转基因斑马鱼来质疑该系统中细胞与细胞相互作用的作用。 紫外线敏感性的退化-大多数鱼类对紫外线有相当的视觉敏感性。这种敏感性在个体发育过程中会降低，正如在鲑鱼和鳟鱼中发现的那样，这与它们的迁徙有关。关于这种损失的自适应值的主要假设在具有不同视觉任务的较大动物中UV敏感性的下降函数。斑马鱼已经被设计来测试一种新的替代假设，即紫外线敏感锥细胞的消失增强了某些视觉介导任务的表现。斑马鱼已经被改造成使得感光细胞类别可以被有条件地消融或失活。这些鱼将在电生理学和行为范例中进行评估，以评估包括波长辨别在内的视觉功能。 合成. 展望未来，我已开始将这三个主题纳入一个总体框架。 不要问“为什么鱼可以再生眼睛和中枢神经系统？”但更有效的问题是“为什么哺乳动物失去了再生眼睛和中枢神经系统的能力？” 我们假设中枢神经系统的再生是适应性的。 我将应用回归进化理论来告知关于失去中枢神经系统再生的适应价值的假设。 我的工作假设是，参与干细胞/再生的基因已经在哺乳动物中被增选为新的功能，包括突触可塑性，学习和记忆。在成年基底脊椎动物中实验性地操纵这些基因是我们在斑马鱼中进行靶向诱变的罕见能力的核心。