title: UNC-6 (netrin) stabilizes oscillatory clustering of the UNC-40 (DCC) receptor to orient polarity.
abstract: 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.
authors.affiliation: Department of Biology, Duke University, Durham, NC 27708.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biology, Duke University, Durham, NC 27708.
authors.forename: Lara M
authors.initials: LM
authors.lastname: Linden
authors.affiliation: Department of Biology, Duke University, Durham, NC 27708.
authors.forename: Kaleb M
authors.initials: KM
authors.lastname: Naegeli
authors.affiliation: Department of Biology, Duke University, Durham, NC 27708.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Ziel
authors.affiliation: Department of Biology, Duke University, Durham, NC 27708.
authors.forename: Qiuyi
authors.initials: Q
authors.lastname: Chi
authors.affiliation: Department of Biology, Duke University, Durham, NC 27708.
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Hagedorn
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, England, UK.
authors.forename: Natasha S
authors.initials: NS
authors.lastname: Savage
authors.affiliation: Department of Biology, Duke University, Durham, NC 27708 david.sherwood@duke.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Sherwood
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism* / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D016764:Cell Polarity; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000502:physiology*; D000075385:Netrins; D055503:Protein Multimerization; D055550:Protein Stability; D021381:Protein Transport; D014599:Uterus / Q000166:cytology
chemical_list: D000199:Actins; D029742:Caenorhabditis elegans Proteins; D015815:Cell Adhesion Molecules; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D000075385:Netrins; C551653:TRIM-9 protein, C elegans; C102174:UNC-40 protein, C elegans; C078146:UNC-6 protein, C elegans