Coordinated cytoskeletal dynamics in skin somatic stem cells - Resubmission 01

描述（由申请人提供）：Wnt信号在皮肤体细胞（SSCs）的维持、激活和谱系承诺中起关键作用。尽管越来越多的证据揭示了细胞骨架和运动蛋白在皮肤发育、组织稳态和伤口修复中的重要性，但细胞骨架动力学如何传递生态位信号来调节皮肤ssc中的Wnt通路仍不清楚。了解这一过程至关重要，因为Wnt通路的缺陷会导致包括癌症在内的各种皮肤疾病。在寻找参与这一过程的潜在细胞骨架调节因子时，我们发现一种哺乳动物谱板蛋白ACF7（肌动蛋白交联因子7）在皮肤ssc中高度富集。我们的初步结果揭示了ACF7及其旁系BPAG1（大疱性类天疱疮抗原1）在皮肤ssc中协调细胞骨架动力学和传递Wnt信号的关键功能。在本提案中，我们将利用我们在皮肤SSCs方面的广泛专业知识进行组合研究，包括ACF7和BPAG1突变动物的体内表征以及潜在的细胞和分子机制的体外研究。特别是，我们将验证一个中心假设，即由ACF7和BPAG1控制的细胞骨架动力学通过Wnt信号通路调节皮肤ssc的功能。从所提出的实验中产生的数据将大大促进我们对皮肤SSC行为的基本机制的理解。此外，我们的研究将有可能导致与皮肤SSCs相关疾病的新治疗方法的发展。

DESCRIPTION (provided by applicant): Wnt signaling plays a critical role in maintenance, activation and lineage commitment of skin somatic stem cells (SSCs). Although accumulating evidence unveils the significance of cytoskeleton and motor proteins in skin development, tissue homeostasis and wound repair, it remains unclear how cytoskeletal dynamics transmit the niche signaling to regulate the Wnt pathway in skin SSCs. Understanding this process is of fundamental importance because defects in the Wnt pathway lead to various skin diseases including cancer. In searching for potential cytoskeletal regulators involved in this process, we found that a mammalian spectraplakin protein, ACF7 (Actin Crosslinking Factor 7), is highly enriched in skin SSCs. Our preliminary results revealed a critical function of ACF7 and its paralog BPAG1 (Bullous Pemphigoid Antigen 1) in coordinating cytoskeletal dynamics and transmitting the Wnt signals in skin SSCs. In this proposal, we will take the advantages of our extensive expertise in skin SSCs to perform a combinatorial study encompassing in vivo characterization of ACF7 and BPAG1 mutant animals and in vitro investigation of the underlying cellular and molecular mechanisms. In particular, we will test a central hypothesis that cytoskeletal dynamics controlled by ACF7 and BPAG1 regulate functions of skin SSCs via the Wnt signaling pathway. Data generated from the proposed experiments will greatly advance our understanding of the basic mechanisms underlying skin SSC behaviors. In addition, our study will potentially lead to the development of novel therapeutic treatments for diseases related to skin SSCs.