Collaborative Research: RUI: Convergent extension in a dynamically patterned epithelium

合作研究：RUI：动态图案化上皮细胞的聚合延伸

• 批准号: 1817873
• 负责人: Terri Williams
• 金额: $ 44.53万
• 依托单位: Trinity College
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1817873&HistoricalAwards=false
• 关键词: Collaborative; Research; RUI; Convergent; extension

For an embryo to develop from a fertilized egg into an adult, cells must elongate in a coordinated and orderly manner. Elongation is required for processes as basic as extending the body axis or as specific as growing the tips of tubules inside of kidneys. This research will examine the process of elongation in the flour beetle, Tribolium, throughout the time that the embryo is forming the repeated parts, called segments, which make up its anterior/posterior body axis. Although an apparently seamless process, previous work showed that segmentation slows down, then speeds up as the body elongates. Corresponding to this switch in rate, cells behave differently during early and late elongation stages. This work will build on those preliminary observations and, first, carefully describe the switch in how clusters of cells elongate and, second, investigate how it is controlled. This kind of discontinuity or switch in tissue elongation in a progressively elongating body axis is unusual and likely to provide insight into novel mechanisms of elongation. The research is a collaborative effort between a type 1 research university and a teaching college. A major impact of this work is to rigorously train undergraduates in interdisciplinary research, combining computer modeling of elongation with hands-on experimental manipulations of the beetle embryo. Undergraduates from the teaching college are linked to the research institution through both on-site visits and extensive online interactions. The hypothesis underlying this work is that the elongating Tribolium embryo represents a tissue that transitions between two mechanisms of convergent extension during early and late stages of embryo elongation. Based on preliminary data, a model of elongation in Tribolium is proposed in which anterior cells undergo ordered intercalation analogous to what is known in Drosophila embryo extension, while posterior cells move in a less orderly fashion relative to neighbors, directed by tissue-level boundaries in the elongating posterior. The work integrates experimental approaches with computational models to test these hypotheses. It combines live imaging of mutant embryos, that differentially affect the alternate models of elongation, with in silico modeling to provide mechanistic insights into Tribolium elongation. This research highlights Tribolium as a new model of elongation. It will develop a basic understanding of the unique genetic and cellular mechanisms that contribute to the discontinuous changes in tissue elongation in Tribolium's progressively elongating body axis. The proposed dynamic feedback between computational models and experiments will improve understanding of how upstream regulatory networks translate into discrete cell behaviors shaping morphogenesis. This work will also allow comparisons to the well-studied insect model, Drosophila, as well as vertebrates, which also elongate progressively. Such comparisons can identify variable versus conserved mechanisms of elongation, providing information about the evolution of fundamental processes that drive morphogenesis. Additionally, the project will generate RNA Seq data, genetic tools, and models of embryo and tissue elongation useful to the community at large.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

对于胚胎从受精卵发育成成人，细胞必须以协调有序的方式伸长。延长是必需的基本过程，如延长身体轴或特定的增长，肾小管内的尖端。这项研究将研究面粉甲虫Tribolium的伸长过程，在胚胎形成重复部分（称为节）的整个过程中，这些部分构成了它的前/后体轴。虽然这是一个看似天衣无缝的过程，但先前的研究表明，随着身体的伸长，分割速度会减慢，然后加快。与这种速率转换相对应的是，细胞在伸长早期和晚期的行为不同。这项工作将建立在这些初步观察的基础上，首先，仔细描述细胞簇如何伸长的开关，其次，研究它是如何控制的。在逐渐伸长的体轴中，组织伸长的这种不连续性或转换是不寻常的，并且可能提供对伸长的新机制的洞察。这项研究是一个类型1研究型大学和教学学院之间的合作努力。这项工作的一个主要影响是严格培训跨学科研究的本科生，将伸长的计算机建模与甲虫胚胎的动手实验操作相结合。教学学院的本科生通过现场访问和广泛的在线互动与研究机构联系在一起。这项工作的假设是，延长赤拟谷盗胚胎代表的组织，在胚胎伸长的早期和晚期阶段之间的两种机制的收敛延伸的过渡。基于初步的数据，Tribolium的伸长模型提出，其中前细胞进行有序的嵌入类似于已知的果蝇胚胎延伸，而后细胞移动在一个不太有序的方式相对于邻居，由组织水平的边界在拉长后。该工作将实验方法与计算模型相结合来测试这些假设。它结合了突变体胚胎的实时成像，差异性地影响了伸长的替代模型，并通过计算机模拟提供了对赤拟谷盗伸长的机理见解。这项研究突出了Tribolium作为一种新的伸长模型。它将发展一个独特的遗传和细胞机制，有助于在赤拟谷盗的逐步延长身体轴组织伸长的不连续变化的基本理解。所提出的计算模型和实验之间的动态反馈将提高上游调控网络如何转化为离散的细胞行为塑造形态发生的理解。这项工作还将允许与研究充分的昆虫模型果蝇以及脊椎动物进行比较，这些动物也逐渐伸长。这样的比较可以识别可变与保守的伸长机制，提供有关驱动形态发生的基本过程的进化信息。此外，该项目将产生RNA Seq数据、遗传工具以及对整个社区有用的胚胎和组织延伸模型。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。