Regulating cell fate and shaping the body plan during morphogenesis and their alteration during oncogenesis

在形态发生过程中调节细胞命运并塑造身体计划及其在肿瘤发生过程中的改变

基本信息

批准号：
10797409
负责人：
Mark A. Peifer
金额：
$ 2.46万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2016-07-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10797409
关键词：
APC gene Actomyosin Address Adherens Junction Adhesions Animals Apical Biological Models Biology Buffers Cell Adhesion Cell Communication Cell Shape Cell membrane Cells Colon Colon Carcinoma Complex Congenital Abnormality Cues Cytoskeleton Defect Development Disease Drosophila genus Embryonic Development Ensure Epithelium Event F-Box Proteins Genetic Goals Homeostasis Human Intercellular Junctions Lead Link Maintenance Malignant Neoplasms Mammalian Cell Microscopy Modeling Molecular Morphogenesis Mutate Mutation Neoplasm Metastasis Organ Phosphotransferases Positioning Attribute Process Property Protein Array Proteins Resistance Shapes Signal Transduction Tissues Tumor Suppressor Proteins WNT Signaling Pathway Work animal tissue cancer initiation cell assembly cell motility detector developmental disease egg gastrulation in vivo protein complex response tool tumorigenesis ubiquitin-protein ligase zygote

项目摘要

7. Abstract One of biology’s central challenges to define the mechanisms by which the single cell zygote assembles itself into the complex body plan of an animal. For the last 27 years we have addressed this fundamental question, following the lead initially provided by the dual functions of bcatenin in cell adhesion and Wnt signaling. We seek to determine how cells assemble polarized tissues and organs and change shape and move during morphogenesis, by coordinating cell adhesion and the cytoskeleton. In parallel, we study Wnt signaling, a paradigm for mechanisms cells use to choose and maintain fate in development and homeostasis and how this goes wrong in disease. We study these events in Drosophila, using its sophisticated genetic tools along with cutting edge microscopy to explore events in vivo, and combine this with work in cultured mammalian cells, to explore conservation and divergence of these mechanisms. Many of the proteins on which we focus are disrupted in human developmental disorders, cancer initiation and metastasis. Currently we explore three key questions in the field. First, we ask how cells initiate and maintain apical-basal polarity, a fundamental property of animal tissues. Cell-cell adherens junctions serve as key polarity landmarks, demarcating the apical and basolateral domains. Our goal is to determine how different upstream inputs are integrated to position adherens junctions during apical-basal polarity establishment, and to define mechanisms ensuring robust polarity maintenance. We hypothesize that the egg plasma membrane and the polarized cytoskeleton it organizes act through multiple effectors to position adherens junctions, with junctional proteins acting as coincidence detectors, and that new mechanisms turn on at gastrulation onset, buffering errors during cellularization. Second, we explore mechanisms by which cell-cell junctions link to the actomyosin cytoskeleton to allow cell shape change without disrupting epithelial integrity. We hypothesize different cells choose from an array of proteins/protein complexes to assemble and link adherens junctions, with different proteins contributing distinct dynamics or force resistance, and that multivalent interactions among the proteins increases robustness. In parallel, we ask how upstream signaling cues drive integrated cytoskeletal responses in morphogenesis, using Abl kinase as a model. Third, we explore how cells choose and maintain fate, using Wnt signaling as a model. We focus on the tumor suppressor Adenomatous polyposis coli (APC), a key negative regulator that is mutated in 80% of colon cancers. Our long-term goal is to determine how APC and its partners in the Wnt-regulatory destruction complex regulate signaling during development and homeostasis, and how that goes wrong in cancer. We hypothesize that the destruction complex is a multimeric machine assembled by polyvalent interactions, that its cellular localization and assembly state are regulated by Wnt signaling acting via regulated Dsh:Axin interactions, and that the F-box protein Slimb/TrCP carries bcatenin to the E3 ligase. This process provides a paradigm for how regulated protein stability regulates cell signaling.

7。摘要生物学定义单细胞合子组装本身的机制的核心挑战之一进入动物的复杂身体计划。在过去的27年中，我们解决了这个基本问题，遵循Bcatenin在细胞粘附和Wnt信号传导中的双重功能最初提供的铅。我们寻求确定细胞如何组装偏振组织和器官，并在形态发生，通过坐标细胞粘附和细胞骨架。同时，我们研究Wnt信号传导细胞用于选择和维持发展和稳态的命运的机制范式以及如何疾病出错。我们使用其复杂的遗传工具以及尖端显微镜以探索体内事件，并将其与培养的哺乳动物细胞中的工作结合到探索这些机制的保护和分歧。我们关注的许多蛋白质是受到人类发育障碍，癌症倡议和转移的破坏。目前，我们探索三个钥匙在现场的问题。首先，我们询问细胞如何启动和维持顶端极性，这是一种基本特性动物组织。细胞 - 细胞粘附连接处是关键的极性地标，划定顶端和基底外侧域。我们的目标是确定如何将不同的上游输入集成到位置顶端极性建立期间的粘附连接，并定义机制确保稳健极性维护。我们假设卵质膜和极化的细胞骨架通过多种效果来组织粘附连接处，连接蛋白的作用巧合探测器，以及新机制在胃开始时打开，在此期间缓冲错误细胞化。其次，我们探索了细胞 - 细胞连接与肌动蛋白细胞骨架的机制允许细胞形状变化而不破坏上皮完整性。我们假设不同的单元从蛋白质/蛋白质复合物阵列组装和连接粘附连接，与不同的蛋白质促进独特的动态或力抗性，以及蛋白质之间的多价相互作用提高鲁棒性。同时，我们询问上游信号提示如何驱动积分的细胞骨架反应在形态发生中，使用ABL激酶作为模型。第三，我们探索细胞如何选择和维持命运，使用 Wnt信号作为模型。我们专注于肿瘤抑制腺瘤性息肉病（APC），这是一个钥匙在80％的结肠癌中突变的负调节剂。我们的长期目标是确定APC和它在WNT调节性破坏复合物中的合作伙伴调节发育和体内平衡期间的信号传导，以及癌症中的错误。我们假设破坏综合体是一台多媒体机器通过多价相互作用组装，其细胞定位和组装状态由Wnt调节信号传导通过调节的DSH：AXIN相互作用，F-box蛋白Slimb/trcp携带bcatenin至 E3连接酶。该过程为调节蛋白质稳定性如何调节细胞信号传导提供了范式。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Modulating apical-basal polarity by building and deconstructing a Yurt.

通过建造和解构蒙古包来调节顶端-基底极性。

DOI：
10.1083/jcb.201810059
发表时间：
2018
期刊：
The Journal of cell biology
影响因子：
0
作者：
Perez-Vale,KiaZ;Peifer,Mark
通讯作者：
Peifer,Mark

Powering morphogenesis: multiscale challenges at the interface of cell adhesion and the cytoskeleton.

DOI：
10.1091/mbc.e21-09-0452
发表时间：
2022-07-01
期刊：
MOLECULAR BIOLOGY OF THE CELL
影响因子：
3.3
作者：
Fernandez-Gonzalez, Rodrigo;Peifer, Mark
通讯作者：
Peifer, Mark

Micron-scale supramolecular myosin arrays help mediate cytoskeletal assembly at mature adherens junctions.

DOI：
10.1083/jcb.202103074
发表时间：
2022-01-03
期刊：
The Journal of cell biology
影响因子：
0
作者：
Yu-Kemp HC;Szymanski RA;Cortes DB;Gadda NC;Lillich ML;Maddox AS;Peifer M
通讯作者：
Peifer M

Scribble and Dlg organize a protection racket to ensure apical-basal polarity.

Scribble 和 Dlg 组织了一个保护球拍以确保顶端-基底极性。

DOI：
10.1073/pnas.2007739117
发表时间：
2020
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Schmidt,Anja;Peifer,Mark
通讯作者：
Peifer,Mark

Rap1 regulates apical contractility to allow embryonic morphogenesis without tissue disruption and acts in part via Canoe-independent mechanisms.

DOI：
10.1091/mbc.e22-05-0176
发表时间：
2023-01-01
期刊：
MOLECULAR BIOLOGY OF THE CELL
影响因子：
3.3
作者：
Perez-Vale, Kia Z.;Yow, Kristi D.;Gurley, Noah J.;Greene, Melissa;Peifer, Mark
通讯作者：
Peifer, Mark