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确定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基本问题， 这是继最初由bcatenin在细胞粘附和Wnt信号传导中的双重功能提供的先导之后。我们 试图确定细胞如何组装极化的组织和器官，并在过程中改变形状和移动。 通过协调细胞粘附和细胞骨架实现形态发生。同时，我们研究Wnt信号， 细胞用来选择和维持发育和稳态中的命运的机制的范例，以及这是如何发生的。 在疾病中出错。我们在果蝇中研究这些事件，使用其复杂的遗传工具，沿着 尖端的显微镜来探索体内的事件，并将其与培养的哺乳动物细胞中的工作相结合， 探索这些机制的保守性和多样性。我们关注的许多蛋白质 在人类发育障碍、癌症发生和转移中被破坏。目前，我们正在探索三个关键 现场提问。首先，我们要问细胞如何启动和维持顶基极性，一个基本的属性 动物组织。细胞-细胞粘附连接是关键的极性标志， 基底外侧区我们的目标是确定如何整合不同的上游投入， 在顶-基底极性建立过程中的粘附连接，并确定确保稳定的 极性保持我们推测，卵质膜和极化的细胞骨架， 组织通过多种效应物定位粘附连接，连接蛋白作为 巧合探测器，新的机制在原肠胚形成开始时打开，缓冲期间的错误， 细胞化其次，我们探索了细胞间连接与肌动球蛋白细胞骨架的机制 以允许细胞形状改变而不破坏上皮完整性。我们假设不同的细胞从一个 蛋白质/蛋白质复合物阵列，用于组装和连接具有不同蛋白质的粘附连接 提供独特的动力学或力阻力，以及蛋白质之间的多价相互作用， 提高鲁棒性。与此同时，我们问上游信号线索如何驱动整合的细胞骨架反应 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， Wnt信号作为模型。我们关注肿瘤抑制基因腺瘤性结肠息肉病（APC）， 在80%的结肠癌中发生突变的负调节因子。我们的长期目标是确定APC和 其在Wnt-调节破坏复合物中的伙伴在发育和体内平衡期间调节信号传导， 以及这在癌症中是如何出错的。我们假设破坏复合体是一个多聚体机器 通过多价相互作用组装，其细胞定位和组装状态受Wnt调控 通过调节Dsh：Axin相互作用的信号传导，以及F-box蛋白Slimb/TrCP携带bcatenin， E3连接酶这一过程为蛋白质稳定性如何调节细胞信号传导提供了一个范例。

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