{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T01:42:47Z","timestamp":1780450967573,"version":"3.54.1"},"reference-count":106,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T00:00:00Z","timestamp":1620950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Microenvironmental signals produced during development or inflammation stimulate lymphatic endothelial cells to undergo lymphangiogenesis, in which they sprout, proliferate, and migrate to expand the vascular network. Many cell types detect changes in extracellular conditions via primary cilia, microtubule-based cellular protrusions that house specialized membrane receptors and signaling complexes. Primary cilia are critical for receipt of extracellular cues from both ligand-receptor pathways and physical forces such as fluid shear stress. Here, we report the presence of primary cilia on immortalized mouse and primary adult human dermal lymphatic endothelial cells <jats:italic>in vitro<\/jats:italic> and on both luminal and abluminal domains of mouse corneal, skin, and mesenteric lymphatic vessels <jats:italic>in vivo<\/jats:italic>. The purpose of this study was to determine the effects of disrupting primary cilia on lymphatic vessel patterning during development and inflammation. Intraflagellar transport protein 20 (IFT20) is part of the transport machinery required for ciliary assembly and function. To disrupt primary ciliary signaling, we generated global and lymphatic endothelium-specific IFT20 knockout mouse models and used immunofluorescence microscopy to quantify changes in lymphatic vessel patterning at E16.5 and in adult suture-mediated corneal lymphangiogenesis. Loss of IFT20 during development resulted in edema, increased and more variable lymphatic vessel caliber and branching, as well as red blood cell-filled lymphatics. We used a corneal suture model to determine ciliation status of lymphatic vessels during acute, recurrent, and tumor-associated inflammatory reactions and wound healing. Primary cilia were present on corneal lymphatics during all of the mechanistically distinct lymphatic patterning events of the model and assembled on lymphatic endothelial cells residing at the limbus, stalk, and vessel tip. Lymphatic-specific deletion of IFT20 cell-autonomously exacerbated acute corneal lymphangiogenesis resulting in increased lymphatic vessel density and branching. These data are the first functional studies of primary cilia on lymphatic endothelial cells and reveal a new dimension in regulation of lymphatic vascular biology.<\/jats:p>","DOI":"10.3389\/fcell.2021.672625","type":"journal-article","created":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T04:13:15Z","timestamp":1620965595000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Loss of Primary Cilia Protein IFT20 Dysregulates Lymphatic Vessel Patterning in Development and Inflammation"],"prefix":"10.3389","volume":"9","author":[{"given":"Delayna","family":"Paulson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Harms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cody","family":"Ward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mackenzie","family":"Latterell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory J.","family":"Pazour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darci M.","family":"Fink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1161\/circresaha.108.192765","article-title":"Ciliary Polycystin-2 Is a Mechanosensitive Calcium Channel Involved in Nitric Oxide Signaling Cascades.","volume":"104","author":"AbouAlaiwi","year":"2009","journal-title":"Circ. Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1007\/s00439-014-1456-y","article-title":"Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome.","volume":"133","author":"Alders","year":"2014","journal-title":"Hum. Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1089\/lrb.2005.3.105","article-title":"Isolation and Characterization of A Novel Mouse Lymphatic Endothelial Cell Line: SV-LEC.","volume":"3","author":"Ando","year":"2005","journal-title":"Lymphat. Res. Biol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"3513","DOI":"10.1038\/onc.2009.220","article-title":"Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer.","volume":"28","author":"Bailey","year":"2009","journal-title":"Oncogene"},{"key":"B5","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1002\/ajmg.c.30231","article-title":"Making sense of cilia in disease: The human ciliopathies.","author":"Baker","year":"2009","journal-title":"Am. J. Medical Genet. Part C Semin. Med. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1172\/jci22037","article-title":"Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation.","volume":"115","author":"Baluk","year":"2005","journal-title":"J. Clin. Invest."},{"key":"B7","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.devcel.2009.06.017","article-title":"Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis.","volume":"17","author":"Bazigou","year":"2009","journal-title":"Dev. Cell"},{"key":"B8","doi-asserted-by":"publisher","first-page":"7347","DOI":"10.1113\/jp274842","article-title":"Calcium and electrical dynamics in lymphatic endothelium.","volume":"595","author":"Behringer","year":"2017","journal-title":"J. Physiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1182\/blood-2010-02-270876","article-title":"Platelets regulate lymphatic vascular development through CLEC-2\u2013SLP-76 signaling.","volume":"116","author":"Bertozzi","year":"2010","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","first-page":"3315","DOI":"10.1172\/jci99027","article-title":"Atypical cadherin Fat4 orchestrates lymphatic endothelial cell polarity in response to flow.","volume":"130","author":"Betterman","year":"2020","journal-title":"J. Clin. Invest."},{"key":"B11","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1161\/atvbaha.116.308020","article-title":"Postnatal Deletion of Podoplanin in Lymphatic Endothelium Results in Blood Filling of the Lymphatic System and Impairs Dendritic Cell Migration to Lymph Nodes.","volume":"37","author":"Bianchi","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"3950","DOI":"10.1167\/iovs.17-21679","article-title":"Novel Insights Into the Phenotypical Spectrum of KIF11-Associated Retinopathy, Including a New Form of Retinal CiliopathyNovel Insights in KIF11-Related Retinopathy.","volume":"58","author":"Birtel","year":"2017","journal-title":"Invest. Ophth. Vis. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"15593","DOI":"10.1073\/pnas.0507865102","article-title":"Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo.","volume":"102","author":"Bj\u00f6rndahl","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3531","DOI":"10.1182\/blood-2005-06-2538","article-title":"Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action.","volume":"107","author":"Cao","year":"2006","journal-title":"Blood"},{"key":"B15","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/j.ccr.2004.08.034","article-title":"PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis.","volume":"6","author":"Cao","year":"2004","journal-title":"Cancer Cell"},{"key":"B16","doi-asserted-by":"publisher","first-page":"15894","DOI":"10.1073\/pnas.1208324109","article-title":"Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis.","volume":"109","author":"Cao","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1454","DOI":"10.1101\/gad.282400.116","article-title":"Mechanotransduction activates canonical Wnt\/\u03b2-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves.","volume":"30","author":"Cha","year":"2016","journal-title":"Genes Dev."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1016\/j.celrep.2016.12.044","article-title":"Cilia Control Vascular Mural Cell Recruitment in Vertebrates.","volume":"18","author":"Chen","year":"2017","journal-title":"Cell Rep."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.125068","article-title":"Piezo1 incorporates mechanical force signals to genetic program that governs lymphatic valve development and maintenance.","volume":"4","author":"Choi","year":"2019","journal-title":"JCI Insight"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1806","DOI":"10.1016\/j.celrep.2013.05.020","article-title":"TGF-\u03b2 Signaling Is Associated with Endocytosis at the Pocket Region of the Primary Cilium.","volume":"3","author":"Clement","year":"2013","journal-title":"Cell Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"3070","DOI":"10.1242\/jcs.049676","article-title":"The primary cilium coordinates early cardiogenesis and hedgehog signaling in cardiomyocyte differentiation.","volume":"122","author":"Clement","year":"2009","journal-title":"J. Cell Sci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/labinvest.2015.147","article-title":"Lymphatic endothelial lineage assemblage during corneal lymphangiogenesis.","volume":"96","author":"Connor","year":"2016","journal-title":"Lab. Invest."},{"key":"B23","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1016\/j.celrep.2014.03.063","article-title":"Pkd1 Regulates Lymphatic Vascular Morphogenesis during Development.","volume":"7","author":"Coxam","year":"2014","journal-title":"Cell Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1097\/01.ico.0000183485.85636.ff","article-title":"Time Course of Angiogenesis and Lymphangiogenesis After Brief Corneal Inflammation.","volume":"25","author":"Cursiefen","year":"2006","journal-title":"Cornea"},{"key":"B25","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.ydbio.2008.04.024","article-title":"Defective remodeling and maturation of the lymphatic vasculature in Angiopoietin-2 deficient mice.","volume":"319","author":"Dellinger","year":"2008","journal-title":"Dev. Biol."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/sdata.2017.106","article-title":"Distinct transcriptional responses of lymphatic endothelial cells to VEGFR-3 and VEGFR-2 stimulation.","volume":"4","author":"Dieterich","year":"2017","journal-title":"Sci. Data"},{"key":"B27","doi-asserted-by":"publisher","first-page":"2806","DOI":"10.1161\/atvbaha.118.311231","article-title":"Characterization of Endothelial Cilia Distribution During Cerebral-Vascular Development in Zebrafish (Danio rerio).","volume":"38","author":"Eisa-Beygi","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1016\/j.cell.2011.05.030","article-title":"A role for the primary cilium in Notch signaling and epidermal differentiation during skin development.","volume":"145","author":"Ezratty","year":"2011","journal-title":"Cell"},{"key":"B29","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1002\/dvdy.24129","article-title":"Murine Notch1 is required for lymphatic vascular morphogenesis during development: Role of Notch1 In Lymphatic Vessel Development.","volume":"243","author":"Fatima","year":"2014","journal-title":"Dev. Dynam."},{"key":"B30","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1038\/s41418-019-0357-y","article-title":"The intraflagellar transport protein IFT20 controls lysosome biogenesis by regulating the post-Golgi transport of acid hydrolases.","volume":"27","author":"Finetti","year":"2020","journal-title":"Cell Death Differ."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1977","article-title":"Intraflagellar transport is required for polarized recycling of the TCR\/CD3 complex to the immune synapse.","volume":"11","author":"Finetti","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0112737","article-title":"Nerve Growth Factor Regulates Neurolymphatic Remodeling during Corneal Inflammation and Resolution.","volume":"9","author":"Fink","year":"2014","journal-title":"PLoS One"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000315","article-title":"The Golgin GMAP210\/TRIP11 anchors IFT20 to the Golgi complex.","volume":"4","author":"Follit","year":"2008","journal-title":"PLoS Genet."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3781","DOI":"10.1091\/mbc.e06-02-0133","article-title":"The Intraflagellar Transport Protein IFT20 Is Associated with the Golgi Complex and Is Required for Cilia Assembly.","volume":"17","author":"Follit","year":"2006","journal-title":"Mol. Biol. Cell"},{"key":"B35","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1038\/nature07391","article-title":"Sox18 induces development of the lymphatic vasculature in mice.","volume":"456","author":"Fran\u00e7ois","year":"2008","journal-title":"Nature"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03959-6","article-title":"Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program.","volume":"9","author":"Frye","year":"2018","journal-title":"Nat. Commun."},{"key":"B37","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/s1534-5807(02)00217-4","article-title":"Angiopoietin-2 Is Required for Postnatal Angiogenesis and Lymphatic Patterning, and Only the Latter Role Is Rescued by Angiopoietin-1.","volume":"3","author":"Gale","year":"2002","journal-title":"Dev. Cell"},{"key":"B38","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/j.ydbio.2015.10.022","article-title":"Multiple mouse models of primary lymphedema exhibit distinct defects in lymphovenous valve development.","volume":"409","author":"Geng","year":"2016","journal-title":"Dev. Biol."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.137652","article-title":"S1PR1 regulates the quiescence of lymphatic vessels by inhibiting laminar shear stress-dependent VEGF-C signaling.","volume":"5","author":"Geng","year":"2020","journal-title":"JCI Insight"},{"key":"B40","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1016\/j.celrep.2014.01.032","article-title":"Endothelial Cilia Mediate Low Flow Sensing during Zebrafish Vascular Development.","volume":"6","author":"Goetz","year":"2014","journal-title":"Cell Rep."},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00684","article-title":"The Importance of Mechanical Forces for in vitro Endothelial Cell Biology.","volume":"11","author":"Gordon","year":"2020","journal-title":"Front. Physiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"2160","DOI":"10.1242\/dev.132704","article-title":"Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway.","volume":"143","author":"Grisanti","year":"2016","journal-title":"Development"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201798271","article-title":"Distinct roles of VE\u2212cadherin for development and maintenance of specific lymph vessel beds.","volume":"37","author":"H\u00e4gerling","year":"2018","journal-title":"EMBO J."},{"key":"B44","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1038\/emboj.2012.340","article-title":"A novel multistep mechanism for initial lymphangiogenesis in mouse embryos based on ultramicroscopy.","volume":"32","author":"H\u00e4gerling","year":"2013","journal-title":"EMBO J."},{"key":"B45","doi-asserted-by":"publisher","first-page":"4843","DOI":"10.1128\/mcb.02214-07","article-title":"Deletion of Vascular Endothelial Growth Factor C (VEGF-C) and VEGF-D Is Not Equivalent to VEGF Receptor 3 Deletion in Mouse Embryos.","volume":"28","author":"Haiko","year":"2008","journal-title":"Mol. Cell Biol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1006\/dbio.2002.0597","article-title":"Efficient Recombination in Diverse Tissues by a Tamoxifen-Inducible Form of Cre: A Tool for Temporally Regulated Gene Activation\/Inactivation in the Mouse.","volume":"244","author":"Hayashi","year":"2001","journal-title":"Dev. Biol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1172\/jci70422","article-title":"Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life.","volume":"124","author":"Hess","year":"2013","journal-title":"J. Clin. Invest."},{"key":"B48","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1681\/asn.2014090856","article-title":"Vascular Endothelial Growth Factor C for Polycystic Kidney Diseases.","volume":"27","author":"Huang","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"11325","DOI":"10.1073\/pnas.0505328102","article-title":"Cilia and Hedgehog responsiveness in the mouse.","volume":"102","author":"Huangfu","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B50","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/nature02061","article-title":"Hedgehog signalling in the mouse requires intraflagellar transport proteins.","volume":"426","author":"Huangfu","year":"2003","journal-title":"Nature"},{"key":"B51","doi-asserted-by":"publisher","first-page":"3749","DOI":"10.1128\/mcb.01387-12","article-title":"Phosphorylation Regulates FOXC2-Mediated Transcription in Lymphatic Endothelial Cells.","volume":"33","author":"Ivanov","year":"2013","journal-title":"Mol. Cell Biol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"3903","DOI":"10.1242\/dev.095026","article-title":"TGF\u03b2 signaling is required for sprouting lymphangiogenesis during lymphatic network development in the skin.","volume":"140","author":"James","year":"2013","journal-title":"Development"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5944","article-title":"TNFR1 mediates TNF-\u03b1-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling.","volume":"5","author":"Ji","year":"2014","journal-title":"Nat. Commun."},{"key":"B54","doi-asserted-by":"publisher","first-page":"3282","DOI":"10.1101\/gad.1727208","article-title":"Lymphatic endothelial cell identity is reversible and its maintenance requires Prox1 activity.","volume":"22","author":"Johnson","year":"2008","journal-title":"Gene Dev."},{"key":"B55","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1083\/jcb.200808137","article-title":"Deletion of IFT20 in the mouse kidney causes misorientation of the mitotic spindle and cystic kidney disease.","volume":"183","author":"Jonassen","year":"2008","journal-title":"J. Cell Biol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1681\/asn.2013121314","article-title":"Endothelial Cilia Are Essential for Developmental Vascular Integrity in Zebrafish.","volume":"26","author":"Kallakuri","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/ni1013","article-title":"Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins.","volume":"5","author":"Karkkainen","year":"2004","journal-title":"Nat. Immunol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"5650","DOI":"10.1182\/blood-2008-09-176776","article-title":"Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution.","volume":"113","author":"Kataru","year":"2009","journal-title":"Blood"},{"key":"B59","doi-asserted-by":"publisher","first-page":"2418","DOI":"10.1016\/j.ajpath.2013.02.025","article-title":"Lymphatic Vessel Memory Stimulated by Recurrent Inflammation.","volume":"182","author":"Kelley","year":"2013","journal-title":"Am. J. Pathol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"1643","DOI":"10.1038\/labinvest.2011.121","article-title":"Regressed lymphatic vessels develop during corneal repair.","volume":"91","author":"Kelley","year":"2011","journal-title":"Lab. Invest."},{"key":"B61","doi-asserted-by":"publisher","first-page":"1857","DOI":"10.1242\/dev.089565","article-title":"Getting out and about: the emergence and morphogenesis of the vertebrate lymphatic vasculature.","volume":"140","author":"Koltowska","year":"2013","journal-title":"Development"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1186\/s13630-015-0016-y","article-title":"The primary cilium functions as a mechanical and calcium signaling nexus.","volume":"4","author":"Lee","year":"2015","journal-title":"Cilia"},{"key":"B63","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1097\/shk.0000000000000961","article-title":"Primary Cilia Deficiency Induces Intracranial Aneurysm.","volume":"49","author":"Liu","year":"2018","journal-title":"Shock"},{"key":"B64","doi-asserted-by":"publisher","first-page":"3176","DOI":"10.1016\/j.celrep.2017.09.006","article-title":"Lymphatic Vessels Balance Viral Dissemination and Immune Activation following Cutaneous Viral Infection.","volume":"20","author":"Loo","year":"2017","journal-title":"Cell Rep."},{"key":"B65","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1083\/jcb.201110132","article-title":"Smooth muscle\u2013endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation.","volume":"197","author":"Lutter","year":"2012","journal-title":"J. Cell Biol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.jdermsci.2013.04.024","article-title":"Activation of the epidermal growth factor receptor promotes lymphangiogenesis in the skin.","volume":"71","author":"Marino","year":"2013","journal-title":"J. Dermatol. Sci."},{"key":"B67","doi-asserted-by":"publisher","first-page":"2363","DOI":"10.1172\/jci23874","article-title":"Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages.","volume":"115","author":"Maruyama","year":"2005","journal-title":"J. Clin. Invest."},{"key":"B68","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/j.cub.2010.02.048","article-title":"Primary cilia regulate branching morphogenesis during mammary gland development.","volume":"20","author":"McDermott","year":"2010","journal-title":"Curr. Biol. CB"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-51381-9","article-title":"Coordination of WNT signaling and ciliogenesis during odontogenesis by piezo type mechanosensitive ion channel component 1.","volume":"9","author":"Miyazaki","year":"2019","journal-title":"Sci. Rep."},{"key":"B70","doi-asserted-by":"publisher","first-page":"4649","DOI":"10.1182\/blood-2004-08-3382","article-title":"Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation.","volume":"105","author":"Morisada","year":"2005","journal-title":"Blood"},{"key":"B71","doi-asserted-by":"publisher","first-page":"2365","DOI":"10.1242\/dev.083865","article-title":"Notch1 functions as a negative regulator of lymphatic endothelial cell differentiation in the venous endothelium.","volume":"140","author":"Murtomaki","year":"2013","journal-title":"Development"},{"key":"B72","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1161\/circulationaha.107.710111","article-title":"Endothelial cilia are fluid shear sensors that regulate calcium signaling and nitric oxide production through polycystin-1.","volume":"117","author":"Nauli","year":"2008","journal-title":"Circulation"},{"key":"B73","doi-asserted-by":"publisher","first-page":"E2589","DOI":"10.1073\/pnas.1519458113","article-title":"Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development.","volume":"113","author":"Noda","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.7554\/elife.53814","article-title":"Shear stimulation of FOXC1 and FOXC2 differentially regulates cytoskeletal activity during lymphatic valve maturation.","volume":"9","author":"Norden","year":"2020","journal-title":"Elife"},{"key":"B75","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1242\/dmm.009340","article-title":"Mouse models of ciliopathies: the state of the art.","volume":"5","author":"Norris","year":"2012","journal-title":"Dis. Model. Mech."},{"key":"B76","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.cell.2020.06.039","article-title":"The Lymphatic Vasculature in the 21st Century: Novel Functional Roles in Homeostasis and Disease.","volume":"182","author":"Oliver","year":"2020","journal-title":"Cell"},{"key":"B77","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1016\/j.ajhg.2011.12.018","article-title":"Mutations in KIF11 Cause Autosomal-Dominant Microcephaly Variably Associated with Congenital Lymphedema and Chorioretinopathy.","volume":"90","author":"Ostergaard","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"B78","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1016\/j.celrep.2014.03.064","article-title":"Polycystin Signaling Is Required for Directed Endothelial Cell Migration and Lymphatic Development.","volume":"7","author":"Outeda","year":"2014","journal-title":"Cell Rep."},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.3390\/cells7120233","article-title":"The Roles of Primary Cilia in Cardiovascular Diseases.","volume":"7","author":"Pala","year":"2018","journal-title":"Cells"},{"key":"B80","doi-asserted-by":"publisher","first-page":"R378","DOI":"10.1016\/s0960-9822(02)00877-1","article-title":"Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease.","volume":"12","author":"Pazour","year":"2002","journal-title":"Curr. Biol."},{"key":"B81","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1083\/jcb.151.3.709","article-title":"Chlamydomonas IFT88 and Its Mouse Homologue, Polycystic Kidney Disease Gene Tg737, Are Required for Assembly of Cilia and Flagella.","volume":"151","author":"Pazour","year":"2000","journal-title":"J. Cell Biol."},{"key":"B82","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1038\/nm1094","article-title":"Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis.","volume":"10","author":"Petrova","year":"2004","journal-title":"Nat. Med."},{"key":"B83","doi-asserted-by":"publisher","first-page":"4593","DOI":"10.1093\/emboj\/cdf470","article-title":"Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor.","volume":"21","author":"Petrova","year":"2002","journal-title":"EMBO J."},{"key":"B84","doi-asserted-by":"publisher","first-page":"2925","DOI":"10.1084\/jem.20091739","article-title":"Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels.","volume":"206","author":"Pflicke","year":"2009","journal-title":"J. Exp. Medicine"},{"key":"B85","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1007\/s00232-001-0075-4","article-title":"Bending the MDCK Cell Primary Cilium Increases Intracellular Calcium.","volume":"184","author":"Praetorius","year":"2001","journal-title":"J. Membr. Biol."},{"key":"B86","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.devcel.2011.12.020","article-title":"Mechanotransduction, PROX1, and FOXC2 Cooperate to Control Connexin37 and Calcineurin during Lymphatic-Valve Formation.","volume":"22","author":"Sabine","year":"2012","journal-title":"Dev. Cell"},{"key":"B87","doi-asserted-by":"publisher","first-page":"3861","DOI":"10.1172\/jci80454","article-title":"FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature.","volume":"125","author":"Sabine","year":"2015","journal-title":"J. Clin. Invest."},{"key":"B88","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1038\/ng.179","article-title":"Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease.","volume":"40","author":"Saburi","year":"2008","journal-title":"Nat. Genet."},{"key":"B89","doi-asserted-by":"publisher","first-page":"5749","DOI":"10.1113\/jp272088","article-title":"Lymphatic pumping: mechanics, mechanisms and malfunction.","volume":"594","author":"Scallan","year":"2016","journal-title":"J. Physiol."},{"key":"B90","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1083\/jcb.201611050","article-title":"IFT20 modulates ciliary PDGFR\u03b1 signaling by regulating the stability of Cbl E3 ubiquitin ligasesIFT20 controls Cbl-mediated inhibition of PDGFR\u03b1.","volume":"217","author":"Schmid","year":"2018","journal-title":"J. Cell Biol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"1861","DOI":"10.1016\/j.cub.2005.09.012","article-title":"PDGFR\u03b1\u03b1 Signaling Is Regulated through the Primary Cilium in Fibroblasts.","volume":"15","author":"Schneider","year":"2005","journal-title":"Curr. Biol."},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00308","article-title":"Inflammation and Lymphatic Function.","volume":"10","author":"Schwager","year":"2019","journal-title":"Front. Immunol."},{"key":"B93","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1038\/84643","article-title":"Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis.","volume":"7","author":"Skobe","year":"2001","journal-title":"Nat. Med."},{"key":"B94","doi-asserted-by":"publisher","first-page":"H507","DOI":"10.1152\/ajpheart.00175.2020","article-title":"TRPV4 channels\u2019 dominant role in the temperature modulation of intrinsic contractility and lymph flow of rat diaphragmatic lymphatics.","volume":"319","author":"Solari","year":"2020","journal-title":"Am. J. Physiol. Heart C"},{"key":"B95","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.1101\/gad.16974811","article-title":"Prox1 dosage controls the number of lymphatic endothelial cell progenitors and the formation of the lymphovenous valves.","volume":"25","author":"Srinivasan","year":"2011","journal-title":"Gene Dev."},{"key":"B96","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1101\/gad.1859310","article-title":"The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells.","volume":"24","author":"Srinivasan","year":"2010","journal-title":"Genes Dev."},{"key":"B97","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1016\/j.celrep.2015.02.026","article-title":"cKit Lineage Hemogenic Endothelium-Derived Cells Contribute to Mesenteric Lymphatic Vessels.","volume":"10","author":"Stanczuk","year":"2015","journal-title":"Cell Rep."},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-020-01462-7","article-title":"Chemokine mediated signalling within arteries promotes vascular smooth muscle cell recruitment.","volume":"3","author":"Stratman","year":"2020","journal-title":"Commun. Biol."},{"key":"B99","doi-asserted-by":"publisher","first-page":"2995","DOI":"10.1172\/jci79386","article-title":"Lymph flow regulates collecting lymphatic vessel maturation in vivo.","volume":"125","author":"Sweet","year":"2015","journal-title":"J. Clin. Invest."},{"key":"B100","doi-asserted-by":"publisher","first-page":"2141","DOI":"10.1084\/jem.20102392","article-title":"DC mobilization from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling.","volume":"208","author":"Tal","year":"2011","journal-title":"J. Exp. Medicine"},{"key":"B101","doi-asserted-by":"publisher","first-page":"4642","DOI":"10.1182\/blood-2004-08-3327","article-title":"Angiopoietin-1 promotes lymphatic sprouting and hyperplasia.","volume":"105","author":"Tammela","year":"2005","journal-title":"Blood"},{"key":"B102","doi-asserted-by":"publisher","first-page":"3997","DOI":"10.1182\/blood-2009-04-216069","article-title":"Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation.","volume":"115","author":"Uhrin","year":"2010","journal-title":"Blood"},{"key":"B103","doi-asserted-by":"publisher","first-page":"1651","DOI":"10.1083\/jcb.201706151","article-title":"Primary cilia sensitize endothelial cells to BMP and prevent excessive vascular regressionPrimary cilium and vascular regression.","volume":"217","author":"Vion","year":"2018","journal-title":"J. Cell Biol."},{"key":"B104","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1016\/s0092-8674(00)81511-1","article-title":"Prox1 Function Is Required for the Development of the Murine Lymphatic System.","volume":"98","author":"Wigle","year":"1999","journal-title":"Cell"},{"key":"B105","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1083\/jcb.200903137","article-title":"Neuropilin-2 mediates VEGF-C\u2013induced lymphatic sprouting together with VEGFR3Nrp-2 mediates lymphatic sprouting.","volume":"188","author":"Xu","year":"2010","journal-title":"J. Cell Biol."},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-70787-4","article-title":"An interphase pool of KIF11 localizes at the basal bodies of primary cilia and a reduction in KIF11 expression alters cilia dynamics.","volume":"10","author":"Zalenski","year":"2020","journal-title":"Sci. Rep."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.672625\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T04:13:20Z","timestamp":1620965600000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.672625\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,14]]},"references-count":106,"alternative-id":["10.3389\/fcell.2021.672625"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.672625","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,14]]},"article-number":"672625"}}