Evolution of Cavefish Eye Degeneration

穴居鱼眼睛退化的进化

• 批准号: 0542384
• 负责人: William Jeffery
• 金额: $ 48万
• 依托单位: University of Maryland, College Park
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0542384&HistoricalAwards=false
• 关键词: Evolution; Cavefish; Eye; Degeneration

Project SummaryIntellectual Merit: The evolutionary and developmental mechanisms responsible for the loss of vision in cave animals are not understood. This proposal continues Dr. Jeffery's research on eye degeneration in the teleost Astyanax mexicanus, which has an eyed surface-dwelling form (surface fish, SF) and many eyeless cave-dwelling forms (cavefish, CF). CF form eye primordia but they arrest in growth and degenerate due to lens apoptosis. The results of his previous grant showed that: (1) Hedgehog (Hh) signaling is enhanced along the CF anterior midline and controls eye degeneration by inducing lens apoptosis, (2) the molecular chaperone Hsp90 is specifically activated in the CF lens and required for lens apoptosis, (3) Hh expression along the embryonic midline is gradually restricted to developing taste buds, and (4) expression of genes positively regulated by Hh signals (e. g. pax2.1a in the optic vesicles and nkx2.1a/b in the neural plate) are expanded in CF. Constructive traits that may compensate for vision, including increases in taste buds, olfactory nerve tracts and bulbs, and the ventral telencephalon and hypothalamus, have also evolved in CF. This continuation proposal explores the hypothesis that eyes have degenerated due to enhanced Hh midline signaling though pleiotrophic positive and negative effects on downstream target genes resulting in developmental tradeoffs between constructive and regressive traits. The specific objectives are: (1) to determine whether Hh signaling controls lens apoptosis by affecting an antagonism between the Dlx5 (and/or Pitx3) and Pax6 transcription factors and/or by regulating Hsp90 expression and coordinately increasing olfactory development, (2 and 3) to determine whether enhanced Hh signaling is responsible for (2) the increased number of taste buds in CF and (3) for enlargement of the ventral telencephalon and hypothalamus in CF, and (4) to determine by genetic analysis whether gustatory, olfactory, and hypothalamic enhancement are coupled to eye degeneration as developmental tradeoffs. Most of the methodologies and reagents to be used in the continued work, including a panel of more than 100 Astyanax cDNAs, have been acquired in the previous grants, and Dr. Jeffery has preliminary results showing that his hypothesis is plausible and ready for more intensive investigation. The results of this study are expected to provide new insights into the mechanisms responsible for CF eye degeneration.Broader Impacts: Studies of cave animals advance discovery and understanding because they provide unique perspectives to research and education in evolutionary developmental biology. Two hypotheses, neutral mutation and natural selection, have been advanced to explain regressive changes such as eye loss in cave animals, but until recently there was little or no experimental support for either of them. These experiments on Astyanax CF are the first to suggest that eye loss is an indirect effect of natural selection on adaptive traits via the positive and negative effects of pleiotropic Hh signals. Pleiotropic effects may have general implications in the evolution of development. In addition to the Hh pathway, other critical developmental signaling pathways have negative and positive regulated targets and the potential to generate evolutionary changes by developmental tradeoffs. The generation of evolutionary changes via pleiotropy is largely underappreciated as a mechanism for directing microevolutionary changes in development, and these studies are designed to shed more light on this process. Another broad impact of this research is the continued integration of research and education, which is accomplished by involving undergraduate students in original research, by training pre-doctoral and post-doctoral investigators, and by the laboratory's outreach to high school science programs. All of these activities include different genders and underrepresented minorities. The cavefish laboratory and colony will continue to be a useful and highly appreciated local resource for teaching and understanding evolutionary biology to high school students, and will also continue to serve as a resource for their short supervised science projects. The degeneration of the cavefish eye is an excellent example of a morphological change that is experimentally tractable, has occurred very recently, and is subject to interpretation through evolutionary theory. Finally, the cavefish colony has an impact beyond this laboratory, serving to support other researchers and springboard the generation of similar colonies internationally.

项目概要知识价值：导致洞穴动物视力丧失的进化和发育机制尚不清楚。这一提议延续了杰弗里博士对硬骨鱼Astyanax mexicanus眼睛退化的研究，该物种有一种有眼睛的表面居住形式（表面鱼，SF）和许多无眼睛的洞穴居住形式（洞穴鱼，CF）。CF形成眼原基，但由于透镜凋亡，它们生长停滞并退化。他以前的赠款结果表明：（1）Hedgehog（Hh）信号传导沿着CF前中线增强，并通过诱导晶状体凋亡来控制眼变性，（2）分子伴侣Hsp 90在CF晶状体中特异性活化，并为晶状体凋亡所需，（3）Hh表达沿着胚胎中线逐渐限于发育中的味蕾，（4）受Hh信号正调控的基因表达（e. G. pax 2.1 a在视泡中，nkx 2.1 a/B在神经板中）在CF中扩增。CF中还进化出了一些可以补偿视觉的结构特征，包括味蕾、嗅神经束和嗅球以及端脑腹侧和下丘脑的增加。该延续建议探索了以下假设：由于增强的Hh中线信号传导，眼睛已经退化，尽管对下游靶基因的多效性积极和消极影响导致建设性和退化性状之间的发育权衡。具体目标是：（1）确定Hh信号传导是否通过影响Dlx 5和Dlx 6之间的拮抗作用来控制透镜凋亡。（和/或Pitx3）和Pax6转录因子和/或通过调节Hsp90表达和协调增加嗅觉发育，（2和3）以确定增强的Hh信号传导是否负责（2）CF中味蕾数量的增加和（3）CF的腹侧端脑和下丘脑的扩大，以及（4）通过遗传分析确定味觉，嗅觉和下丘脑的增强是否与眼退化相关联作为发育权衡。在继续工作中使用的大多数方法和试剂，包括一组100多个Astyanax cDNA，已经在以前的资助中获得，Jeffery博士的初步结果表明他的假设是合理的，并准备进行更深入的调查。这项研究的结果预计将提供新的见解的机制负责CF眼degeneration.Broader影响：洞穴动物的研究推进发现和理解，因为它们提供了独特的视角，在进化发育生物学的研究和教育。中性突变和自然选择这两种假说已经被提出来解释洞穴动物眼睛丧失等退化性变化，但直到最近，这两种假说都很少或根本没有实验支持。这些对Astyanax CF的实验首次表明，眼睛丧失是自然选择通过多效性Hh信号的正效应和负效应对适应性性状的间接影响。多效性效应可能对发展的演变产生普遍影响。除了Hh通路，其他关键的发育信号传导通路具有负调控和正调控的靶点，并有可能通过发育权衡产生进化变化。通过多效性产生的进化变化在很大程度上被低估为一种指导发育中微进化变化的机制，这些研究旨在更多地阐明这一过程。这项研究的另一个广泛影响是研究和教育的持续整合，这是通过让本科生参与原创研究，通过培训博士前和博士后研究人员，以及实验室对高中科学课程的推广来实现的。所有这些活动都包括不同性别和代表性不足的少数群体。洞穴鱼实验室和殖民地将继续是一个有用的和高度赞赏的地方资源，用于教学和理解进化生物学高中学生，也将继续作为他们的短期监督科学项目的资源。洞穴鱼眼睛的退化是一个很好的例子，说明了一种形态学上的变化，这种变化在实验上是容易处理的，是最近才发生的，并且可以通过进化论来解释。最后，洞穴鱼群体的影响超出了这个实验室，有助于支持其他研究人员，并为国际上类似群体的产生提供跳板。