Cell polarity and morphogenesis in Xenopus embryos

爪蟾胚胎的细胞极性和形态发生

• 批准号: 10406539
• 负责人: Sergei Sokol
• 金额: $ 48.12万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406539
• 关键词: Actomyosin; Biochemical; Biological; Birth; Cell Polarity; Cell Shape; Cells; Cilia; Congenital Abnormality; Cues; Development; Developmental Process; Disease; Disseminated Malignant Neoplasm; Drosophila genus; Embryo; Epithelial; Event; Experimental Models; Genes; Genetic study; Health; Human; Knowledge; Left; Link; Metastatic to; Molecular; Morphogenesis; Movement; Myosin Type II; Neural Tube Closure; Pathway interactions; Pattern; Polycystic Kidney Diseases; Positioning Attribute; Prevention; Proteins; Proteomics; Renal carcinoma; Signal Pathway; Signal Transduction; Syndrome; System; Systems Biology; Techniques; Tissues; Translating; Vertebrates; Xenopus; cell behavior; cell motility; experience; gastrulation; high resolution imaging; mechanical force; planar cell polarity; polarized cell; programs; protein complex; response; transcriptomics; vertebrate embryos

Project summary In the early vertebrate embryo, signaling pathways instruct cell fates and orchestrate morphogenetic movements, placing cells into proper positions to experience new rounds of signaling and new waves of fate specification and morphogenesis. A long standing question remains how changes in cell polarity determine collective cell behaviors during early development. To approach this problem, this program focuses on the core planar cell polarity (PCP) pathway that is one of the main drivers of morphogenetic processes in vertebrates. Core PCP proteins have been discovered in Drosophila genetic studies. In vertebrates, the PCP protein complexes Vangl/Pk/Celsr and Fz/Dvl/Celsr are conserved and accumulate at opposite cell edges along the body axis, marking tissue polarity. The significance of the core PCP proteins extends far beyond being epithelial polarity markers, as their vertebrate homologs function in key developmental processes, including gastrulation movements, neural tube closure and branching morphogenesis, the formation of functional cilia and left-right patterning. To gain mechanistic knowledge of morphogenetic events, including vertebrate gastrulation, we will study the following long-standing questions in the field: a) how cells polarize in response to a cue, b) how the cell polarity translates into spatially restricted activation of effectors such as Myosin II, and c) how actomyosin contractions and the resulting mechanical forces alter cell shape and coordinate collective cell movements. New force-dependent genes that are involved in the control of morphogenesis will be identified. These directions will be pursued using high resolution imaging, embryological and molecular biological techniques combined with systems level analysis (proteomics and transcriptomics). Our studies will use Xenopus embryos as our main experimental model, due to their fast external development, ease of experimental manipulation and large size allowing biochemical and systems biology approaches. The proposed studies will advance the knowledge of basic cell biological mechanisms underlying vertebrate morphogenesis. High relevance to human health is due to the known connections of PCP signaling to multiple congenital defects and syndromes, polycystic kidney disease and cancers.

项目总结 在早期脊椎动物胚胎中，信号通路指导细胞命运并协调 形态发生运动，将细胞放置在适当的位置以体验新一轮的 信号和命运指定和形态发生的新浪潮。一个长期存在的问题 仍然是细胞极性的变化如何决定早期发育中的集体细胞行为。 为了解决这个问题，这个程序集中在核心平面细胞极性(PCP)途径上 是脊椎动物形态发生过程的主要驱动力之一。核心PCP蛋白有 是在果蝇遗传学研究中发现的。在脊椎动物中，PCP蛋白质复合体 Vangl/Pk/Celsr和Fz/DVL/Celsr是保守的，并积累在沿 身体轴，标记组织的极性。核心PCP蛋白的意义远远超出了 作为上皮极性标志，作为它们的脊椎动物同源物在关键发育过程中发挥作用 过程，包括原肠运动、神经管闭合和分支形态发生， 功能性纤毛的形成和左右排列。获得机械方面的知识 形态发生事件，包括脊椎动物的原肠发育，我们将研究以下长期存在的问题 该领域的问题：a)细胞如何极化以响应提示，b)细胞极性如何转换 到空间受限的效应器的激活，如肌球蛋白II，以及c)肌球蛋白如何收缩 由此产生的机械力改变了细胞的形状，协调了集体细胞的运动。 参与形态发生控制的新的力依赖基因将被识别出来。 这些方向将利用高分辨率成像、胚胎学和分子学进行研究。 生物技术与系统水平分析(蛋白质组学和转录组学)相结合。我们的 研究将使用非洲爪哇胚胎作为我们的主要实验模型，因为它们快速的外部 开发，易于实验操作和大尺寸，允许生化和系统 生物学走近了。建议的研究将提高对基本细胞生物学的认识 脊椎动物形态发生的机制。与人类健康高度相关的原因是 已知PCP信号与多个先天性缺陷和综合征，多囊 肾脏疾病和癌症。