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

• 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
• 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

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 生物学的核心挑战之一是定义单细胞受精卵自我组装的机制 动物复杂的身体结构。在过去的27年里，我们一直在解决这个根本问题， 遵循最初由bcatenin在细胞黏附和Wnt信号转导中的双重功能提供的先导。我们 寻求确定细胞如何组装极化的组织和器官，以及如何在 形态发生，通过协调细胞黏附和细胞骨架。同时，我们研究了Wnt信号，一个 细胞在发育和动态平衡中选择和维持命运的机制的范例及其如何 在疾病中出了问题。我们研究了果蝇的这些事件，使用其复杂的遗传工具以及 探索活体事件的尖端显微镜，并将其与培养的哺乳动物细胞相结合，以 探索这些机制的保守性和发散性。我们关注的许多蛋白质是 在人类发育障碍、癌症的启动和转移中受到干扰。目前，我们探索了三个关键 在现场的问题。首先，我们问细胞如何启动和维持心尖-基极，这是一种基本属性 动物组织。细胞-细胞黏附连接作为关键的极性标志，区分根尖和 基底侧域。我们的目标是确定如何集成不同的上游投入以定位 在根尖-基极建立过程中坚持连接，并确定确保健壮的机制 维持极性。我们假设卵细胞质膜和极化的细胞骨架 组织通过多个效应器来定位粘连连接，连接蛋白充当 符合探测器，以及新的机制在原肠形成开始时开启，缓冲 细胞化。第二，我们探索了细胞间连接到肌动蛋白细胞骨架的机制。 允许细胞在不破坏上皮完整性的情况下改变形状。我们假设不同的细胞从一个 一系列蛋白质/蛋白质复合体，用于组装和连接粘连连接，与不同的蛋白质 提供了不同的动力或阻力，蛋白质之间的多价相互作用 增强健壮性。同时，我们询问上游信号信号如何驱动整合的细胞骨架反应。 在形态发生上，以Abl激酶为模型。第三，我们探索细胞如何选择和维持命运，使用 WNT信令作为模型。我们关注的是抑癌基因--结肠腺瘤性息肉病(APC) 负调控因子在80%的结肠癌中发生突变。我们的长期目标是确定APC和 它在WNT-调节破坏复合体中的合作伙伴在发育和动态平衡期间调节信号， 以及这在癌症中是如何出错的。我们假设毁灭复合体是一台多聚体机器 通过多价相互作用组装，其细胞定位和组装状态受Wnt调控 通过受调控的Dsh：Axin相互作用起作用的信号，以及F-box蛋白SLimb/TrCP携带bcatenin到 E3连接酶。这一过程为调节蛋白质稳定性如何调节细胞信号提供了一个范例。

项目成果

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
• 作者: Perez-Vale,KiaZ;Peifer,Mark
• 通讯作者: Peifer,Mark

The Dilute domain of Canoe is not essential for Canoe's role in linking adherens junctions to the cytoskeleton but contributes to robustness of morphogenesis.

Canoe 的稀释结构域对于 Canoe 连接粘附连接与细胞骨架的作用不是必需的，但有助于形态发生的稳健性。

• DOI: 10.1101/2023.10.18.562854
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: McParland,EmilyD;AmberButcher,T;Gurley,NoahJ;Johnson,RuthI;Slep,KevinC;Peifer,Mark
• 通讯作者: Peifer,Mark

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

动力形态发生：细胞粘附和细胞骨架界面的多尺度挑战。

• 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
• 作者: Yu-Kemp HC;Szymanski RA;Cortes DB;Gadda NC;Lillich ML;Maddox AS;Peifer M
• 通讯作者: Peifer M

To condense or not to condense: Wnt regulation by centrosome-nucleated biomolecular condensates.

• DOI: 10.1073/pnas.2213905119
• 发表时间: 2022-10-11
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Peifer, Mark