微丝极性组装调控不对称细胞分裂的机制研究

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。

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.