基底膜位于上皮的基底部，对多种组织器官发生及结构的维系起重要作用。许多基因突变会导致基底膜缺陷相关疾病，包括表皮，肾脏，血管和肌肉组织等。基底膜由细胞外基质蛋白沿细胞顶底轴定向分泌与组装形成。目前有关基底膜蛋白的定向分泌与组装的调控机制还知之甚少。我们在眼的附属器官-鼻泪管的发生过程中发现Wnt-PCP通路核心蛋白Prickle1的缺失会导致细胞外基质蛋白异位表达和基底膜形成失败，暗示Wnt-PCP通路指导基底膜蛋白的极性运输。我们同时发现Prickle1在iPS分化而来的胚体类器官的基底膜形成过程中起类似的作用，提示体外分化的胚体组织很可能是研究基底膜形成的一个重要模型。本项目将利用体外分化的类胚体模型对Wnt-PCP在基底膜的形成过程中与微管的定向组装及Rab蛋白参与的囊泡定向运输的关系进行探讨，研究结果深化基底膜定向分泌与组装机制，为临床相关疾病的治疗提供科学依据。

The basement membrane (BM) is located at the base of multiple epithelial tissues, which plays crucial role in organogenesis and structural maintenance. Mutations of BM-related genes often lead to tissue lesions, including that of epidermis, kidney, blood vessels and muscle tissues. Currently, mechanisms of polarized BM secretion and assembly remain largely unknown. We found that disruption of Prickle1, a key component of Wnt-PCP signaling, in developing tear duct led to ectopic BM matrices deposition and failure of BM formation, suggesting that Wnt-PCP likely directs polarized BM protein trafficking. Similar defects were also detected in embryoid organoids derived from Prickle1 mutant iPS cells, which lend us an unique in vitro model to study basement membrane formation. In this proposal, we will utilize embryoid organoids to understand the role of Prickle1 mediated Wnt-PCP in directed microtubule assembly and polarized Rab vesicles’ trafficking. The expected outcomes will deepen our understanding of polarized BM secretion and assembly, and thus lay a foundation for treatment of the BM-related diseases.