Browsing by Author "Ziel, Joshua W"

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    Roles for UNC-6/Netrin Signaling During Cell Invasion in C. Elegans
    (2011) Ziel, Joshua W

    Basement membranes are dense, sheet-like forms of extracellular matrix that

    surround the epithelial tissues of metazoan organisms. While these structures are

    critical for epithelial support and tissue organization, basement membranes also pose

    formidable barriers to most cells. However, certain specialized cells are able to breach

    these barriers and move between tissues. Acquisition of cell invasive behavior by some

    tumor cells is thought be an important step in cancer progression. Due to the clear basic

    and clinical importance of understanding the mechanisms underlying cell invasion

    through basement membranes, cell invasive behaviors has been an area of intense study.

    In this work I examine a developmentally regulated model of cell invasive behavior in

    the nematode worm, C. elegans. In this system a single proto-epithelial cell remodels

    basement membrane to connect two epithelial tissues, the uterus and vulva. Using this

    model I identify a novel role for UNC-6/Netrin signaling during this process through basement membranes. I show that Netrin signaling is a third regulatory input for AC invasion that functions partially in parallel to fos-1a and the vulval signal. Further I link netrin signaling to the formation of invasive protrusions that penetrate basement membrane.

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    UNC-6 (netrin) stabilizes oscillatory clustering of the UNC-40 (DCC) receptor to orient polarity.
    (J Cell Biol, 2014-09-01) Wang, Zheng; Linden, Lara M; Naegeli, Kaleb M; Ziel, Joshua W; Chi, Qiuyi; Hagedorn, Elliott J; Savage, Natasha S; Sherwood, David R
    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.