The causes and consequences of cell division asymmetries

细胞分裂不对称的原因和后果

• 批准号: BB/R009732/1
• 负责人: Buzz Baum
• 金额: $ 55.1万
• 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: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR009732%2F1
• 关键词: causes; consequences; cell; division; asymmetries

While manufactured objects tend to be built by putting together different parts of fixed size, like lego bricks, living systems are constructed by cell growth and division. In fact, all the cells in a multicellular animal, like a human or fly, are derived in this way from a single fertilised egg cell. How then do organisms generate the cell type diversity required to build complex organs and tissues? This is achieved in part from cell divisions that are asymmetric - as single cells divide to generate siblings that take up different fates as the result of asymmetries in their inheritance or in their environment. While the asymmetric segregation of molecules that help to determine differences in sibling cell fate have been studied in detail, many of these divisions are also characterised by reproducible differences in sibling cell size and shape. How and why this is the case is not understood. To shed light on this, here we aim to study the regulation and function of the differences in cell mass, volume and surface area that arise from asymmetries in the division process.Although the importance of the size and shape of an animal cell for its behavior and function has been recognised for at least 100 years, since D'Arcy Thompson, little work has been done to quantify the variation in sibling cell size and shape, to define the mechanisms that underlie division errors, nor their contribution to cell behavior and function. Nevertheless, the fact that reproducible differences in sibling cell size and shape are frequently associated with asymmetric stem cell divisions, suggests that they are likely to be important. This is probably more significant in the context of organ development, where cells with different fates must work together as a functional unit. A good example of this is the developing fly bristle, where four cells generated via a series of asymmetric divisions form a complex three dimensional structure that functions in mechanosensation. Here, taking advantage of recent advances in imaging, we aim to use two complementary model systems, mammalian cells in culture and cells of the fly bristle lineage to determine: i) sources of error that affect the distribution of cell mass and volume at division during both symmetric and asymmetric divisions, ii) the points at which errors in division symmetry are corrected in both cases (differences between cells mustn't be eliminated during asymmetric divisions), and iii) the functions of asymmetries in the size and shape of sibling cells in the context of organogenesis. Moreover, in the case of the bristle, where cells must wrap around one another in order to form a functional organ, we will explore the extent to which differences in the volume and apical surface area of individual cells generated by asymmetries in division are corrected or amplified. Overall, we expect our analysis to have an important impact on our understanding of conserved elements of the division process that determine its accuracy, and to shed light on the function of size and shape differences between sibling cells in the context of organogenesis. We also expect this work to have implications for our understanding of stem cell divisions in humans, many of which are thought to be asymmetric, and for cancer research since cancer cells frequently exhibit a profound loss of cell size homeostasis.

人造物体往往是由固定大小的不同部分组合而成，就像乐高积木一样，而生命系统是由细胞生长和分裂构成的。事实上，多细胞动物的所有细胞，如人类或苍蝇，都是以这种方式从单个受精卵细胞中衍生出来的。那么，生物体如何产生构建复杂器官和组织所需的细胞类型多样性呢？这在一定程度上是由于细胞分裂是不对称的——单个细胞分裂产生的兄弟姐妹由于遗传或环境的不对称而承担着不同的命运。虽然分子的不对称分离有助于确定兄弟细胞命运的差异已经被详细研究，但许多这些分裂也以兄弟细胞大小和形状的可复制差异为特征。目前还不清楚这种情况是如何发生的，以及为什么会发生。为了阐明这一点，我们的目标是研究分裂过程中不对称引起的细胞质量、体积和表面积差异的调节和功能。尽管动物细胞的大小和形状对其行为和功能的重要性已经被认识了至少100年，但自达西·汤普森以来，几乎没有人做过量化兄弟细胞大小和形状的变化，来定义分裂错误的机制，也没有做过它们对细胞行为和功能的贡献。然而，兄弟姐妹细胞大小和形状的可复制差异经常与不对称干细胞分裂有关，这表明它们可能很重要。这在器官发育的背景下可能更为重要，因为不同命运的细胞必须作为一个功能单位一起工作。一个很好的例子就是发育中的苍蝇鬃毛，通过一系列不对称分裂产生的四个细胞形成了一个复杂的三维结构，在机械感觉中起作用。在这里，利用成像的最新进展，我们的目标是使用两个互补的模型系统，哺乳动物细胞培养和苍蝇刚毛谱系的细胞来确定：1)在对称和非对称分裂过程中影响细胞质量和体积分布的误差来源，2)在这两种情况下，分裂对称性误差被纠正的点（细胞之间的差异在不对称分裂过程中不能消除），以及3)在器官发生的背景下，兄弟细胞大小和形状的不对称性的功能。此外，在刚毛的情况下，细胞必须相互缠绕才能形成一个功能器官，我们将探索由分裂不对称产生的单个细胞的体积和顶表面积的差异在多大程度上被纠正或放大。总的来说，我们期望我们的分析对我们对分裂过程中决定其准确性的保守元素的理解产生重要影响，并阐明在器官发生的背景下兄弟细胞之间大小和形状差异的功能。我们还希望这项工作对我们理解人类干细胞分裂（其中许多被认为是不对称的）和癌症研究有启示，因为癌细胞经常表现出细胞大小稳态的严重丧失。

项目成果

Oncogenic Ras deregulates cell-substrate interactions during mitotic rounding and respreading to alter cell division orientation

致癌 Ras 在有丝分裂变圆和重新扩散过程中解除细胞与基质相互作用的调节，从而改变细胞分裂方向

• DOI: 10.1101/2023.01.12.523730
• 发表时间: 2023
• 作者: Ganguli S

Polarized SCAR and the Arp2/3 complex regulate apical cortical remodeling in asymmetrically dividing neuroblasts.

• DOI: 10.1016/j.isci.2023.107129
• 发表时间: 2023-07-21
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Cazzagon, Giulia;Roubinet, Chantal;Baum, Buzz
• 通讯作者: Baum, Buzz

SCAR and the Arp2/3 complex polarise the actomyosin cortex and plasma membrane organization in asymmetrically dividing neuroblasts

SCAR 和 Arp2/3 复合物使不对称分裂神经母细胞中的肌动球蛋白皮质和质膜组织极化

• DOI: 10.1101/2023.01.05.522888
• 发表时间: 2023
• 作者: Cazzagon G

Oncogenic Ras deregulates cell-substrate interactions during mitotic rounding and respreading to alter cell division orientation.

• DOI: 10.1016/j.cub.2023.05.061
• 发表时间: 2023-07-10
• 期刊: Current biology : CB
• 作者: Ganguli S;Wyatt T;Nyga A;Lawson RH;Meyer T;Baum B;Matthews HK
• 通讯作者: Matthews HK

Mechanochemical Crosstalk Produces Cell-Intrinsic Patterning of the Cortex to Orient the Mitotic Spindle.

• DOI: 10.1016/j.cub.2020.06.098
• 发表时间: 2020-09-21
• 期刊: Current biology : CB
• 作者: Dimitracopoulos A;Srivastava P;Chaigne A;Win Z;Shlomovitz R;Lancaster OM;Le Berre M;Piel M;Franze K;Salbreux G;Baum B
• 通讯作者: Baum B