Mitotic cell mechanics in a tissue context

组织背景下的有丝分裂细胞力学

• 批准号: BB/K009001/1
• 负责人: Buzz Baum
• 金额: $ 44.95万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK009001%2F1
• 关键词: Mitotic; cell; mechanics; tissue; context

Both symmetric and asymmetric cell divisions require a complex set of molecular processes to ensure the proper orientation of the microtubule-based spindle with respect to cortical cues. In asymmetric divisions, cells first establish an axis of polarity in response to internal or external cues. This is then read by astral microtubules to orient the spindle to segregate cell fate determinants asymmetrically in the two daughter cells. In symmetric divisions, the spindle typically reads apical-basal polarity cues and mitotic cell shape in order to align in such a way as to divide to release tissue strain. In both cases, spindle orientation is likely to be important for high fidelity chromosome segregation. Understanding the role of mechanics in mitosis is therefore a fundamental problem in cell biology. In addition, it is currently thought that controlled ratio of symmetric versus asymmetric cell division plays a critical role in stem cell homeostasis, a phenomenon thought to be misregulated in cancer.While much progress has been made in identifying biochemical signalling pathways that regulate cell division in general, little is known about the mechanisms by which normal epithelial cells and stem cells sense, respond to and resist forces. Only recently the role of force has been studied in spindle orientation of individual adherent cells, and mechanical stress is known to be a major external signal involved in epithelial cell regulation. Our preliminary data now show that forces also play a significant role in spindle orientation in tissues. Building on this work we plan to test how spindle orientation responds to external force during symmetric and asymmetric divisions and to identify the molecular machinery involved.To do so we will explore the molecular and cellular mechanisms by which mitotic cells sense, respond to and resist mechanical forces using two complementary experimental systems developed in the Baum and Charras labs: i) a device that enables the mechanical perturbation of MDCK epithelial monolayers, and ii) the Drosophila notum, a tissue where genetics, mechanical perturbations and live imaging can be readily combined. In this way, we expect to identify conserved molecular mechanisms that ensure that cell division occurs with high fidelity in the context of an epithelium subject tochanges in mechanics. We will further test whether force also a play a role in asymmetric divisions (as a simple model of stem cell divisions).We expect this work to have a significant impact on our understanding of fundamental questions in the fields of cell division, tissue homeostasis, stem cell biology and regenerative medicine. There are several lines of evidence that make clear the importance of bridging this gap in our understanding of the role of mechanics in cell division. First, passage through mitosis involves dramatic active changes in cell shape and cortical rigidity, which when perturbed may lead to cell division failure and chromosome mis-segregation; potentially contributing to cancer development. Second, the ability of a cell to divide and form a colony in a mechanically soft medium is a key test of cellular transformation and malignancy, implying a role for mechanics in cell division. Third, in cell culture the mitotic spindle typically aligns parallel to a substrate plane along the axis of greatest tensile force. Fourth, it is possible that symmetrical divisions which tend to increase the number of stem cells will be triggered by tensile stress. In this way tissues may respond directly to the need for more cells by increasing the number of cells via tensile-controlled proliferation combined to oriented cell division ensuring relieve of the tension across the tissue.

对称和不对称的细胞分裂都需要一套复杂的分子过程，以确保基于微管的纺锤体相对于皮层线索的正确取向。在不对称分裂中，细胞首先建立一个极性轴，以响应内部或外部线索。然后，这是由星形微管读取，以定向纺锤体分离细胞的命运决定因素不对称的两个子细胞。在对称分裂中，纺锤体通常读取顶部-基部极性线索和有丝分裂细胞形状，以便以这样的方式排列，从而分裂以释放组织应变。在这两种情况下，纺锤体方向可能是重要的高保真染色体分离。因此，了解力学在有丝分裂中的作用是细胞生物学中的一个基本问题。此外，目前认为，控制对称与不对称细胞分裂的比例在干细胞稳态中起着关键作用，这种现象被认为在癌症中被错误调节。虽然在确定一般调节细胞分裂的生化信号通路方面取得了很大进展，但对正常上皮细胞和干细胞感知、响应和抵抗力的机制知之甚少。直到最近，人们才研究了力在单个贴壁细胞纺锤体方向中的作用，并且已知机械应力是参与上皮细胞调节的主要外部信号。我们的初步数据现在表明，力也在组织中的纺锤体取向中起着重要作用。在这项工作的基础上，我们计划测试在对称和不对称分裂过程中纺锤体方向如何响应外力，并确定所涉及的分子机制。为此，我们将使用Baum和Charras实验室开发的两个互补实验系统探索有丝分裂细胞感知、响应和抵抗机械力的分子和细胞机制：i）能够机械扰动MDCK上皮单层的装置，和ii）果蝇背，遗传学、机械扰动和活体成像可以容易地组合的组织。通过这种方式，我们希望确定保守的分子机制，确保细胞分裂发生高保真的背景下，上皮细胞受到力学的变化。我们将进一步测试力是否也在不对称分裂中发挥作用（作为干细胞分裂的一个简单模型）。我们希望这项工作对我们理解细胞分裂，组织稳态，干细胞生物学和再生医学领域的基本问题产生重大影响。有几条证据表明，在我们理解细胞分裂中力学作用的过程中，弥合这一差距的重要性。首先，通过有丝分裂涉及细胞形状和皮质刚性的急剧变化，当受到干扰时可能导致细胞分裂失败和染色体错误分离;可能导致癌症发展。第二，细胞在机械软介质中分裂和形成集落的能力是细胞转化和恶性的关键测试，这意味着机械在细胞分裂中的作用。第三，在细胞培养中，有丝分裂纺锤体通常沿着最大张力的轴沿着平行于基底平面排列。第四，可能的是，趋向于增加干细胞数量的对称分裂将由张应力触发。以这种方式，组织可以通过张力控制的增殖与定向细胞分裂相结合来增加细胞数量，从而直接响应对更多细胞的需求，从而确保缓解整个组织的张力。

项目成果

Myosin II Controls Junction Fluctuations to Guide Epithelial Tissue Ordering.

• DOI: 10.1016/j.devcel.2017.09.018
• 发表时间: 2017-11-20
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Curran S;Strandkvist C;Bathmann J;de Gennes M;Kabla A;Salbreux G;Baum B
• 通讯作者: Baum B

Oriented Division: Using T-Junctions to Determine Direction.

定向划分：使用丁字路口确定方向。

• DOI: 10.1016/j.cub.2016.03.046
• 发表时间: 2016
• 期刊: CB
• 作者: Dimitracopoulos A

MOESM1 of Changes in ESCRT-III filament geometry drive membrane remodelling and fission in silico

MOESM1 的 ESCRT-III 丝几何形状变化驱动膜重塑和硅片裂变

• DOI: 10.6084/m9.figshare.10027169
• 发表时间: 2019
• 作者: Harker-Kirschneck L

Coordinated control of Notch/Delta signalling and cell cycle progression drives lateral inhibition-mediated tissue patterning.

• DOI: 10.1242/dev.134213
• 发表时间: 2016-07-01
• 期刊: Development (Cambridge, England)
• 作者: Hunter GL;Hadjivasiliou Z;Bonin H;He L;Perrimon N;Charras G;Baum B
• 通讯作者: Baum B

Myosin II controls junction fluctuations to guide epithelial tissue ordering

肌球蛋白 II 控制连接波动以指导上皮组织排序

• DOI: 10.1101/078204
• 发表时间: 2016
• 作者: Curran S