细胞迁移是生命活动的基本特征，参与多种生理和病理过程。细胞膜随机极化的内在性质是形成细胞迁移结构的基础，赋予细胞随机迁移的潜力；然而，在体内环境中，胞外信号引导细胞膜沿信号方向发生极化，促使细胞进行定向迁移。目前对于细胞在定向迁移中如何克服自发的膜动态，维持迁移方向稳定性的机制尚不清楚。在对线虫Q神经前体细胞发育的研究中，申请人发现Hippo激酶的缺失导致Q细胞不能沿线虫的前后体轴进行定向迁移，而发生异常的向背腹体轴方向的偏移。申请人的生化实验结果表明Hippo激酶通过磷酸化微丝骨架关键调控因子小G蛋白MIG-2/RhoG来维持迁移方向的稳定性。本课题拟以此为基础，结合CRISPR-Cas9基因编辑技术、活体荧光显微成像技术以及生化分析，鉴定维持细胞迁移方向稳定性的关键因子，揭示迁移极性稳定的调控机制，为理解细胞迁移以及相关疾病的预防治疗提供新线索。

Cell migration is involved many physiological and pathological processes. Random motility depends on the cellular intrinsic ability to form spontaneous membrane protrusions at various directions. Most cell migrations in vivo are directional, in which the cell morphology is polarized and motility is orientated towards the extracellular cues. Despite the profound importance of directional cell migration in live animals, little is known about how a steered migrating cell inhibits the spontaneous membrane protrusions outside the leading edge. Here we address the problem using the C. elegans Q neuroblasts which undergo directional migrations along the anteroposterior (A/P) body axis. Our preliminary results have shown that mutations of Hippo kinases disrupted the persistent direction of Q cell migration and caused the abnormal polarization of Q cells towards the dorsal-ventral body axis. Our biochemical analysis uncovered that the C. elegans Hippo kinases directly phosphorylate a small GTPas MIG-2/RhoG, altering its activity in the assembly of the actin cytoskeleton in migrating cells. We will combine the CRISPR-Cas9-based genome editing technique, live cell imaging and biochemistry to understand the function of Hippo-MIG-2 signaling axis in directional cell migration. We also prepare to identify other key modulators that stabilize migration direction and reveal the underlying molecular and cellular regulatory mechanisms. We expect that our results will provide novel insights into directional cell migration and migration-related diseases.