UNC-6 (netrin) stabilizes oscillatory clustering of the UNC-40 (DCC) receptor to orient polarity.
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The receptor deleted in colorectal cancer (DCC) directs dynamic polarizing activities in animals toward its extracellular ligand netrin. How DCC polarizes toward netrin is poorly understood. By performing live-cell imaging of the DCC orthologue UNC-40 during anchor cell invasion in Caenorhabditis elegans, we have found that UNC-40 clusters, recruits F-actin effectors, and generates F-actin in the absence of UNC-6 (netrin). Time-lapse analyses revealed that UNC-40 clusters assemble, disassemble, and reform at periodic intervals in different regions of the cell membrane. This oscillatory behavior indicates that UNC-40 clusters through a mechanism involving interlinked positive (formation) and negative (disassembly) feedback. We show that endogenous UNC-6 and ectopically provided UNC-6 orient and stabilize UNC-40 clustering. Furthermore, the UNC-40-binding protein MADD-2 (a TRIM family protein) promotes ligand-independent clustering and robust UNC-40 polarization toward UNC-6. Together, our data suggest that UNC-6 (netrin) directs polarized responses by stabilizing UNC-40 clustering. We propose that ligand-independent UNC-40 clustering provides a robust and adaptable mechanism to polarize toward netrin.
Published Version (Please cite this version)
Wang, Zheng, Lara M Linden, Kaleb M Naegeli, Joshua W Ziel, Qiuyi Chi, Elliott J Hagedorn, Natasha S Savage, David R Sherwood, et al. (2014). UNC-6 (netrin) stabilizes oscillatory clustering of the UNC-40 (DCC) receptor to orient polarity. J Cell Biol, 206(5). pp. 619–633. 10.1083/jcb.201405026 Retrieved from https://hdl.handle.net/10161/9026.
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The Sherwood lab is interested in understanding mechanisms that drive dynamic cellular behaviors underlying normal development and human disease. We study 1) How cells invade into tissues, 2) How stem cells interact with their niches, and 3) How cells control and interact with extracellular matrix. Our lab primarily examines C. elegans development, in which simple cellular complexity, amenability to genetics/genomics/transgenics/molecular perturbations, and evolutionary comparisons facilitates powerful insights. One particular emphasis of our work is live-cell imaging, where we watch cellular behaviors and cell-extracellular matrix interactions unfold in real-time to understand their regulation and function. Cell invasion, stem cell regulation, and cell-matrix interactions are fundamental to development, regeneration, cancer, and aging. Our work aims to advance our understanding of these fascinating processes and positively influence human health.
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