title: The netrin receptor DCC focuses invadopodia-driven basement membrane transmigration in vivo.
abstract: Though critical to normal development and cancer metastasis, how cells traverse basement membranes is poorly understood. A central impediment has been the challenge of visualizing invasive cell interactions with basement membrane in vivo. By developing live-cell imaging methods to follow anchor cell (AC) invasion in Caenorhabditis elegans, we identify F-actin-based invadopodia that breach basement membrane. When an invadopodium penetrates basement membrane, it rapidly transitions into a stable invasive process that expands the breach and crosses into the vulval tissue. We find that the netrin receptor UNC-40 (DCC) specifically enriches at the site of basement membrane breach and that activation by UNC-6 (netrin) directs focused F-actin formation, generating the invasive protrusion and the cessation of invadopodia. Using optical highlighting of basement membrane components, we further demonstrate that rather than relying solely on proteolytic dissolution, the AC's protrusion physically displaces basement membrane. These studies reveal an UNC-40-mediated morphogenetic transition at the cell-basement membrane interface that directs invading cells across basement membrane barriers.
authors.affiliation: Department of Biology, Duke University, Durham, NC 27708, USA.
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Hagedorn
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Ziel
authors.forename: Meghan A
authors.initials: MA
authors.lastname: Morrissey
authors.forename: Lara M
authors.initials: LM
authors.lastname: Linden
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Qiuyi
authors.initials: Q
authors.lastname: Chi
authors.forename: Sam A
authors.initials: SA
authors.lastname: Johnson
authors.forename: David R
authors.initials: DR
authors.lastname: Sherwood
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001485:Basement Membrane / Q000166:cytology / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000075385:Netrins; D011554:Pseudopodia / Q000378:metabolism*; D014844:Vulva / Q000166:cytology / Q000254:growth & development / Q000378:metabolism
chemical_list: D000199:Actins; D029742:Caenorhabditis elegans Proteins; D015815:Cell Adhesion Molecules; D009419:Nerve Tissue Proteins; D000075385:Netrins; C102174:UNC-40 protein, C elegans; C078146:UNC-6 protein, C elegans; D049452:Green Fluorescent Proteins