{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T07:54:25Z","timestamp":1793692465564,"version":"4.5.1"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,8,17]],"date-time":"2017-08-17T00:00:00Z","timestamp":1502928000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,8,17]],"date-time":"2017-08-17T00:00:00Z","timestamp":1502928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Macrophage interactions with other cells, either locally or at distances, are imperative in both normal and pathological conditions. While soluble means of communication can transmit signals between different cells, it does not account for all long distance macrophage interactions. Recently described tunneling nanotubes (TNTs) are membranous channels that connect cells together and allow for transfer of signals, vesicles, and organelles. However, very little is known about the mechanism by which these structures are formed. Here we investigated the signaling pathways involved in TNT formation by macrophages using multiple imaging techniques including super-resolution microscopy (3D-SIM) and live-cell imaging including the use of FRET-based Rho GTPase biosensors. We found that formation of TNTs required the activity and differential localization of Cdc42 and Rac1. The downstream Rho GTPase effectors mediating actin polymerization through Arp2\/3 nucleation, Wiskott-Aldrich syndrome protein (WASP) and WASP family verprolin-homologous 2 (WAVE2) proteins are also important, and both pathways act together during TNT biogenesis. Finally, TNT function as measured by transfer of cellular material between cells was reduced following depletion of a single factor demonstrating the importance of these factors in TNTs. Given that the characterization of TNT formation is still unclear in the field; this study provides new insights and would enhance the understanding of TNT formation towards investigating new markers.<\/jats:p>","DOI":"10.1038\/s41598-017-08950-7","type":"journal-article","created":{"date-parts":[[2017,8,11]],"date-time":"2017-08-11T07:16:32Z","timestamp":1502435792000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":177,"title":["The Role of Rho-GTPases and actin polymerization during Macrophage Tunneling Nanotube Biogenesis"],"prefix":"10.1038","volume":"7","author":[{"given":"Samer J.","family":"Hanna","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kessler","family":"McCoy-Simandle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Miskolci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Cammer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9188-7580","authenticated-orcid":false,"given":"Louis","family":"Hodgson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0591-9767","authenticated-orcid":false,"given":"Dianne","family":"Cox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,8,17]]},"reference":[{"key":"8950_CR1","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.it.2004.03.007","volume":"25","author":"DM Davis","year":"2004","unstructured":"Davis, D. M. & Dustin, M. L. What is the importance of the immunological synapse? Trends in immunology \n                           25, 323\u2013327, doi:10.1016\/j.it.2004.03.007 (2004).","journal-title":"Trends in immunology"},{"key":"8950_CR2","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1126\/science.1093133","volume":"303","author":"A Rustom","year":"2004","unstructured":"Rustom, A., Saffrich, R., Markovic, I., Walther, P. & Gerdes, H. H. Nanotubular highways for intercellular organelle transport. Science \n                           303, 1007\u20131010, doi:10.1126\/science.1093133 (2004).","journal-title":"Science"},{"key":"8950_CR3","doi-asserted-by":"crossref","unstructured":"Onfelt, B. et al. Structurally distinct membrane nanotubes between human macrophages support long-distance vesicular traffic or surfing of bacteria. J Immunol \n                           177, 8476\u20138483, doi:177\/12\/8476 (2006).","DOI":"10.4049\/jimmunol.177.12.8476"},{"key":"8950_CR4","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.immuni.2005.08.009","volume":"23","author":"SC Watkins","year":"2005","unstructured":"Watkins, S. C. & Salter, R. D. Functional connectivity between immune cells mediated by tunneling nanotubules. Immunity \n                           23, 309\u2013318, doi:10.1016\/j.immuni.2005.08.009 (2005).","journal-title":"Immunity"},{"key":"8950_CR5","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1385\/IR:36:1:211","volume":"36","author":"RD Salter","year":"2006","unstructured":"Salter, R. D. & Watkins, S. C. Dynamic properties of antigen uptake and communication between dendritic cells. Immunologic research \n                           36, 211\u2013220, doi:10.1385\/IR:36:1:211 (2006).","journal-title":"Immunologic research"},{"key":"8950_CR6","doi-asserted-by":"publisher","first-page":"17194","DOI":"10.1073\/pnas.1006785107","volume":"107","author":"X Wang","year":"2010","unstructured":"Wang, X., Veruki, M. L., Bukoreshtliev, N. V., Hartveit, E. & Gerdes, H. H. Animal cells connected by nanotubes can be electrically coupled through interposed gap-junction channels. Proceedings of the National Academy of Sciences of the United States of America \n                           107, 17194\u201317199, doi:10.1073\/pnas.1006785107 (2010).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"8950_CR7","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.4049\/jimmunol.173.3.1511","volume":"173","author":"B Onfelt","year":"2004","unstructured":"Onfelt, B., Nedvetzki, S., Yanagi, K. & Davis, D. M. Cutting edge: Membrane nanotubes connect immune cells. J Immunol \n                           173, 1511\u20131513 (2004).","journal-title":"J Immunol"},{"key":"8950_CR8","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/ncb1682","volume":"10","author":"S Sowinski","year":"2008","unstructured":"Sowinski, S. et al. Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV-1 transmission. Nature cell biology \n                           10, 211\u2013219, doi:10.1038\/ncb1682 (2008).","journal-title":"Nature cell biology"},{"key":"8950_CR9","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2012.00072","volume":"3","author":"L Marzo","year":"2012","unstructured":"Marzo, L., Gousset, K. & Zurzolo, C. Multifaceted roles of tunneling nanotubes in intercellular communication. 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