Characterizing the fundamental mechanisms of epithelial invagination during ocular morphogenesis

描述眼形态发生过程中上皮内陷的基本机制

基本信息

批准号：
9978822
负责人：
Timothy F Plageman
金额：
$ 38.5万
依托单位：
OHIO STATE 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：
2016-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978822
关键词：
Affect Apical Area Cell Density Cell Shape Cell physiology Cells Complex Congenital Abnormality Contracts Crystalline Lens Data Development Embryo Embryonic Development Epithelial Epithelial Cells Epithelium Event Extracellular Matrix Eye Eye Development Generations Geometry Goals Growth Hair follicle structure Image Individual Knowledge Labyrinth Lead Lens Placodes Mechanics Mediating Methods Microscopy Monitor Morphogenesis Movement Mus Nature Optics Organ Phenotype Pituitary Gland Process Proteins Public Health Publishing Radial Regenerative Medicine Resolution Role Shapes Structural defect Structure Surface Testing Thyroid Gland Time Tissues Vesicle Vision body system cell behavior cell motility constriction density driving force experimental study fluorescence imaging gastrulation lens lens morphogenesis member mutant polarized cell

项目摘要

Project Summary Generation of the eye, more so than many organs, requires precise control of its shape for optimal function. Obtaining knowledge of how the eye and lens is constructed during embryonic development is therefore important to help describe the nature of ocular abnormalities that lead to major structural defects or more subtle changes that alter vision. An example of a morphogenetic event required for the generation of organs is epithelial invagination. This process drives the inward bending of epithelia of several early organ systems including that of the lens placode during early ocular development. Although several mechanisms have been proposed to drive this process, such as apical constriction or local placodal growth, none have been found sufficient to account for epithelial bending. We have recently observed that placodal cells change shape, move, and generate cytoskeletal structures in a planar polarized manner that produces a net flow of cells toward the central placode. One of the hallmarks of planar-polarized cell movements such as these is the formation and resolution of cellular rosettes, an organized process of cell rearrangement that requires spatial restriction of junctional proteins that contract and shorten junctions and proteins that lengthen and stabilize cellular junctions. We have identified planar-polarized localization of proteins responsible for junctional contraction (Shroom3 and p120-catenin) and stabilization (Par3 and cdc42). These results led us to our central hypothesis that invagination is driven by a combination of epithelial cell movements and anisotropic cell shape changes organized by radial planar polarized protein localization, junction contraction, and junction elongation. We will test this central hypothesis with three aims utilizing live-fluorescent microscopy of genetically altered mouse embryos. In aim 1 we will characterize the role of anisotropic junctional contraction and analyze the consequences of combined deficiency of Shroom3 and p120 catenin. The goal of aim 2 is to characterize the role of Par3 in junction elongation during rosette resolution and invagination. Aim 3 will investigate whether anisotropic cell geometry and movement results from the mutual antagonism between proteins that induce junctional contraction and junctional elongation. Once completed, the experiments in this proposal will define the cell behaviors that drive the mechanisms of lens placode invagination.

项目概要与许多器官相比，眼睛的生成更需要精确控制其形状以实现最佳功能。因此，了解胚胎发育过程中眼睛和晶状体是如何构造的对于帮助描述导致主要结构缺陷或更多缺陷的眼部异常的性质很重要改变视力的微妙变化。器官生成所需的形态发生事件的一个例子是上皮内陷。这个过程驱动几个早期器官系统的上皮向内弯曲包括早期眼睛发育期间的晶状体基板。尽管已经建立了多种机制提议驱动这一过程，例如顶端收缩或局部基板生长，但尚未发现足以解释上皮弯曲。我们最近观察到基板细胞改变形状，以平面极化方式移动并生成细胞骨架结构，从而产生细胞的净流动朝向中央基板。诸如此类的平面极化细胞运动的标志之一是细胞玫瑰花结的形成和分解，细胞重排的有组织过程，需要空间限制收缩和缩短连接的连接蛋白以及延长和稳定的蛋白质细胞连接。我们已经确定了负责连接的蛋白质的平面偏振定位收缩（Shroom3 和 p120-catenin）和稳定（Par3 和 cdc42）。这些结果引导我们中心假设是内陷是由上皮细胞运动和各向异性细胞共同驱动的由径向平面极化蛋白质定位、连接收缩和连接组织的形状变化伸长。我们将利用活体荧光显微镜测试这一中心假设的三个目标转基因小鼠胚胎。在目标 1 中，我们将描述各向异性连接收缩的作用并分析 Shroom3 和 p120 连环蛋白联合缺乏的后果。目标 2 的目标是描述 Par3 在玫瑰花结分解和内陷过程中连接伸长中的作用。目标3将研究各向异性细胞几何形状和运动是否是由于细胞之间的相互拮抗作用造成的诱导连接收缩和连接伸长的蛋白质。完成后，本实验该提案将定义驱动晶状体基板内陷机制的细胞行为。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Thyroid bud morphogenesis requires CDC42- and SHROOM3-dependent apical constriction.

甲状腺芽形态发生需要 CDC42 和 SHROOM3 依赖的顶端收缩。

DOI：
发表时间：
2016-01-15
期刊：
影响因子：
2.4
作者：
Loebel, David A F;Plageman Jr, Timothy F;Tang, Theresa L;Jones, Vanessa J;Muccioli, Maria;Tam, Patrick P L
通讯作者：
Tam, Patrick P L

Arvcf Dependent Adherens Junction Stability is Required to Prevent Age-Related Cortical Cataracts.

Arvcf 依赖性粘附连接稳定性是预防年龄相关性皮质白内障所必需的。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Martin, Jessica B;Herman, Kenneth;Houssin, Nathalie S;Rich, Wade;Reilly, Matthew A;Plageman Jr, Timothy F
通讯作者：
Plageman Jr, Timothy F

Focal adhesion kinase (FAK) expression and activation during lens development

晶状体发育过程中粘着斑激酶 (FAK) 的表达和激活