溶血磷脂酸受体（LPAR2a/2b/3）在斑马鱼后侧线原基的集体细胞迁移和MET中的作用及机制

集体细胞迁移在胚胎发育、组织再生和肿瘤转移中均有重要作用，然而目前对其定向迁移和形态形成的机制仍所知甚少。 斑马鱼的侧线是一个研究集体细胞迁移的良好模型。 在胚胎发育中，后侧线原基（pLLP）通过集体细胞迁移和间充质-上皮转化（MET）在迁移路径上留下多组细胞形成前神经丘。我们在前期工作中发现溶血磷脂酸受体LPAR2a/2b/3在斑马鱼胚胎的后侧线系统高表达，下调其表达导致前神经丘发育异常，提示LPAR2a/2b/3可能参与pLLP内的MET过程。 因此本项目拟构建LPAR2a/2b/3 下调或突变的斑马鱼模型，并鉴别由此导致的侧线系统发育表型，最终确定LPAR2a/2b/3的下游信号通路及表型产生的分子机理。 该研究不仅有助于理解LPA信号通路调控集体细胞迁移和形态形成的机理，对治疗和预防某些恶性肿瘤的转移也能提供新的思路。

Collective cell migration is critical for animal development, tissue repair and cancer metastasis. However, the mechanisms underlying the directional migration and morphogenesis during this process remain elusive, largely due to the difficulty to visualize this migration in vivo. The zebrafish posterior lateral line is an excellent model for studying collective cell migration. During zebrafish development, the posterior lateral line primordium (pLLP) migrates as a cohort from the head towards the tip of the tail. The pLLP undergoes a tissue rearrangement through a process called mesenchymal-epithelial transition (MET), whereby cells in the leading region gradually adopt an epithelial shape to form rosette-like structures (protoneuromasts) in the trailing region. These rosettes are then periodically separated and deposited along the trunk to form proneuromasts. In our preliminary experiments, we found that lysophosphatidic acid receptors (LPAR2a/2b/3) are highly expressed in the posterior lateral line in zebrafish embryos. Knocking down their expression resulted in abnormal rosette-like structures in the pLLP and fewer neuromasts, probably due to defects in the MET. Therefore, the aims of this proposal are: 1) Establish the zebrafish models of LPAR2a/2b/3 knocking down or mutation; 2) Identify the phenotypes in posterior lateral line development, particularly defects in collective cell migration and MET in the pLLP in these models; and 3) Determine the downstream signaling pathways of LPAR2a/2b/3 in lateral line development, and their underlying molecular mechanism. This work will not only unveil a novel, LPA-mediated mechanism for regulating collective cell migration and morphogenesis, but also provide new conceptual framework for preventing and treating cancer metastasis.