微丝极性组装调控不对称细胞分裂的机制研究

Asymmetric cell division (ACD) generates two cells with different fates, and is the cellular basis for cell diversity and tissue homeostasis. Distinct types of cells adopt different mechanisms to accomplish ACD. Here, we found an asymmetric division in the Caenorhabditis elegans Q.p neuroblast that began with a slightly posteriorly displaced mitotic spindle and myosin was equally distributed in the ingressing furrow during cytokinesis. However, the anterior of the dividing cell progressively expands, producing a smaller posterior daughter that undergoes apoptosis and a larger anterior daughter that divides and differentiates into neurons. The enlargement of daughter cell asymmetry may require a spindle- and myosin-independent factor. The proposed study aims to elucidate cellular and molecular mechanism underlying ACD of Q.p neuroblast. Our preliminary results have shown that, more F-actin and WAVE-Arp2/3 accumulated anteriorly during this division. Indeed, inhibition of actin polymerization or equal actin assembly on the cortex created symmetric division and allowed the survival and neuronal differentiation of the posterior daughter. The anteriorly polarized actin assembly was regulated by the Wnt signaling pathway and small G proteins. We will further investigate the extracellular cue that polarizes Q.p neuroblast and characterize the signaling pathway that's conveys the extracellular signal to cortical actin polymerization. Our results will advance our understanding of ACD and provide novel insights into ACD-related diseases.

细胞不对称分裂产生两个不同命运的子细胞，是产生细胞多样性和维持成体组织稳态的基础。不同类型细胞采用迥异的方式实现不对称分裂。线虫Q.p神经前体细胞在胞质分裂过程中细胞前端逐步扩张，在前端产生大的子细胞最终形成神经元，而在后端产生小的子细胞进入凋亡程序。Q.p细胞分裂始于轻度向后偏移的纺锤体，肌球蛋白均匀分布于收缩环，暗示子细胞不对称性的扩增需要独立于纺锤体和肌球蛋白的未知因子。本课题拟揭示Q.p细胞不对称分裂的新调控机制。我们发现微丝在分裂的Q.p细胞前端极性组装，微丝成核因子不对称的富集在细胞前端，破坏微丝的极性组装会导致对称分裂，改变子细胞的大小和命运。我们初步发现Wnt信号通过Frizzled受体和小G蛋白调控微丝在细胞前端的极性组装，我们将深入探索建立神经前体细胞不对称分裂过程中细胞极性的胞外信号和传导通路。本课题的研究成果将加深对细胞不对称分裂的理解，为防治相关疾病提供新思路。

不对称细胞分裂产生两个具有相同遗传物质但不同命运的子细胞，是机体发育与组织稳态的细胞基础。不同的细胞谱系可能采用不同的分裂机制完成不对称细胞分裂，本课题以秀丽隐杆线虫的Q神经前体细胞为研究对象，发现一种调控不对称细胞分裂新机制。我们发现在Q.p细胞分裂从一个不对称定位的纺锤体开始，两个子细胞的大小差异在胞质分裂过程中不断增加，最终较小的子细胞发生凋亡。我们发现依赖于Arp2/3的F-actin在分裂过程中在Q.p细胞前端皮层聚集，这表明F-actin聚合产生的不对称扩张力可使前子细胞增大。抑制皮层肌动蛋白的聚合或人为诱导肌动蛋白在细胞皮层的对称组装都可导致Q.p进行对称细胞分裂。此外，破坏Wnt信号通路导致细胞皮层的肌动蛋白组装异常并引起细胞对称分裂。APC/APR-1响应Wnt信号在Q.p细胞前端皮层不对称地分布并促进肌动蛋白的极化组装。综上，我们的结果表明Wnt信号通路通过在分裂细胞中极化皮层肌动蛋白的聚合来建立子细胞不对称性。“不对称微丝聚合促进不对称细胞分裂”的新模型为不对称分裂调控机制的理解，为其相关疾病提供新思路。

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