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.
Skin stem cells play an important role in skin development and wound response. Aberrant regulation of skin stem cell functions leads to various diseases including skin cancer. In response to constant mechanical stress, skin cells develop a unique and elaborate cytoskeletal system. However, little is known about the role of cytoskeletal dynamics in skin stem cells. Our proposed research will employ a comprehensive approach encompassing mouse genetics and molecular and cellular biology to decipher the mechanisms whereby coordinated cytoskeletal dynamics regulate key developmental pathways in skin stem cells. Our results will provide an important basis for development of rationally based, molecularly targeted drugs against diseases involving defects in skin stem cells.
|Yue, Jiping; Zhang, Yao; Liang, Wenguang G et al. (2016) In vivo epidermal migration requires focal adhesion targeting of ACF7. Nat Commun 7:11692|
|Yuan, Fuqiang; Chen, Xiaopan; Liu, Jie et al. (2016) Up-regulation of Siah1 by ethanol triggers apoptosis in neural crest cells through p38 MAPK-mediated activation of p53 signaling pathway. Arch Toxicol :|
|Chen, Xiaopan; Liu, Jie; Feng, Wen-ke et al. (2015) MiR-125b protects against ethanol-induced apoptosis in neural crest cells and mouse embryos by targeting Bak 1 and PUMA. Exp Neurol 271:104-11|
|Liu, Han; Yue, Jiping; Lei, Qiang et al. (2015) Ultraviolet B Inhibits Skin Wound Healing by Affecting Focal Adhesion Dynamics. Photochem Photobiol 91:909-16|
|Liu, Han; Yue, Jiping; Huang, He et al. (2015) Regulation of Focal Adhesion Dynamics and Cell Motility by the EB2 and Hax1 Protein Complex. J Biol Chem 290:30771-82|
|Yue, Jiping; Xie, Min; Gou, Xuewen et al. (2014) Microtubules regulate focal adhesion dynamics through MAP4K4. Dev Cell 31:572-85|