Cell Polarity and Cytokinesis

 描述（由申请人提供）：胞质分裂和细胞极性缺陷与人类疾病（如癌症）相关，但它们之间可能的因果关系尚不清楚。胞质分裂是一个细胞物理分裂为两个，通过构建由丝状肌动蛋白和运动肌球蛋白-II组成的收缩环来完成。当两个子细胞接受相同的细胞质和皮质成分并继承相同的细胞命运时，分裂被称为对称。然而，在许多特化细胞分裂中，例如在胚胎发生期间和在干细胞中，分裂是不对称的，导致具有不同细胞命运和/或不同大小的子细胞。在动物细胞中，不对称分裂由PAR蛋白（PARtititioning deficient）控制，PAR蛋白定位于细胞皮层，并确保每个子细胞获得适当的细胞命运决定因素。PAR蛋白被认为通过决定有丝分裂纺锤体的位置和方向间接调节不对称细胞分裂，然后定位肌动球蛋白收缩环以驱动细胞分裂。然而，我们的初步数据表明，PAR蛋白也直接促进胞质分裂，通过增加收缩环组装和收缩的鲁棒性。在 梭在线虫受精卵中，PAR蛋白定位于不同的前（aPAR）和后（pPAR）皮质和细胞质结构域以建立前-后轴。我们发现，无论是皮质的aPARs或pPARs的损失增强细胞质分裂失败率的突变体与减弱收缩环。此外，我们发现PAR蛋白促进丝状肌动蛋白和肌球蛋白-II的收缩环的招聘。基于这些数据，我们的中心假设是PAR蛋白通过促进收缩环收缩的鲁棒性来防止胞质分裂失败。在这个提议中，我们将从三个方面确定介导这种对胞质分裂失败的保护的分子机制：1）我们将鉴定极性机制的特定分子组分（2）我们将确定PAR蛋白保护胞质分裂失败的细胞机制; 3）我们将确定PAR蛋白在多细胞环境中胚胎发生过程中是否在保护胞质分裂中发挥更普遍的作用。由于胞质分裂失败和细胞极性失调都受到进化上保守的分子机制的调节，并且都是人类疾病（如癌症）的生物标志物，因此我们的工作将与人类健康相关。

 DESCRIPTION (provided by applicant): Defects in both cytokinesis and cell polarity are associated with human disease such as cancer but the possible causal link between them remains unknown. Cytokinesis is the physical division of one cell into two, accomplished by the construction of a contractile ring composed of filamentous actin and the motor myosin-II. When the two daughter cells receive the same cytoplasmic and cortical components and inherit the same cell fate, the division is referred to as symmetric. However, in many specialized cell divisions, such as during embryogenesis and in stem cells, division is asymmetric, resulting in daughter cells with different cell fates and/or of different sizes. In animal cells, asymmetric division is controlled by the PAR proteins (PARtitioning defective), which localize to the cell cortex and ensure each daughter cell receives the proper cell fate determinants. The PAR proteins are thought to regulate asymmetric cell division indirectly by dictating the position and orientation of the mitotic spindle, which then positions the actomyosin contractile ring to drive cell division. However, our preliminary data suggests that the PAR proteins also promote cytokinesis directly by increasing the robustness of contractile ring assembly and constriction. In the C. elegans zygote, the PAR proteins localize to distinct anterior (aPARs) and posterior (pPARs) cortical and cytoplasmic domains to establish the anterior-posterior axis. We found that loss of either the cortical aPARs or pPARs enhanced the cytokinesis failure rate in mutants with weakened contractile rings. Further, we found that the PAR proteins promote the recruitment of filamentous actin and myosin-II to the contractile ring. Based on these data, our central hypothesis is that the PAR proteins protect against cytokinesis failure by contributing to the robustness of contractile ring constriction. In this proposal, we will determine the molecular mechanisms that mediate this protection against cytokinesis failure in three ways: 1) We will identify the specific molecular components of the polarity machinery (PAR proteins and PAR interacting proteins) that are required for cytokinesis protection; 2) we will determine the cellulr mechanism(s) of protection from cytokinesis failure by the PAR proteins; and 3) we will determine if PAR proteins play a more general role in protecting cytokinesis during embryogenesis in a multicellular context. As both cytokinesis failure and dysregulation of cell polarity are regulated by evolutionarily conserved molecular mechanisms and both are emerging as biomarkers for human diseases such as cancer, our work will have relevance for human health.