Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow

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dc.contributor.authorBetterman, K.L.
dc.contributor.authorSutton, D.L.
dc.contributor.authorSecker, G.A.
dc.contributor.authorKazenwadel, J.
dc.contributor.authorOszmiana, A.
dc.contributor.authorLim, L.
dc.contributor.authorMiura, N.
dc.contributor.authorSorokin, L.
dc.contributor.authorHogan, B.M.
dc.contributor.authorKahn, M.L.
dc.contributor.authorMcNeill, H.
dc.contributor.authorHarvey, N.L.
dc.date.issued2020
dc.description.abstractThe atypical cadherin FAT4 has established roles in the regulation of planar cell polarity and Hippo pathway signaling that are cell context dependent. The recent identification of FAT4 mutations in Hennekam syndrome, features of which include lymphedema, lymphangiectasia, and mental retardation, uncovered an important role for FAT4 in the lymphatic vasculature. Hennekam syndrome is also caused by mutations in collagen and calcium binding EGF domains 1 (CCBE1) and ADAM metallopeptidase with thrombospondin type 1 motif 3 (ADAMTS3), encoding a matrix protein and protease, respectively, that regulate activity of the key prolymphangiogenic VEGF-C/VEGFR3 signaling axis by facilitating the proteolytic cleavage and activation of VEGF-C. The fact that FAT4, CCBE1, and ADAMTS3 mutations underlie Hennekam syndrome suggested that all 3 genes might function in a common pathway. We identified FAT4 as a target gene of GATA-binding protein 2 (GATA2), a key transcriptional regulator of lymphatic vascular development and, in particular, lymphatic vessel valve development. Here, we demonstrate that FAT4 functions in a lymphatic endothelial cell-autonomous manner to control cell polarity in response to flow and is required for lymphatic vessel morphogenesis throughout development. Our data reveal a crucial role for FAT4 in lymphangiogenesis and shed light on the mechanistic basis by which FAT4 mutations underlie a human lymphedema syndrome.
dc.description.statementofresponsibilityKelly L. Betterman, Drew L. Sutton, Genevieve A. Secker, Jan Kazenwadel, Anna Oszmiana ... Natasha Harvey ... et al.
dc.identifier.citationJournal of Clinical Investigation, 2020; 130(6):3315-3328
dc.identifier.doi10.1172/JCI99027
dc.identifier.issn0021-9738
dc.identifier.issn1558-8238
dc.identifier.orcidHarvey, N.L. [0000-0001-9839-8966]
dc.identifier.urihttp://hdl.handle.net/2440/130184
dc.language.isoen
dc.publisherAmerican Society for Clinical Investigation
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1061365
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1146352
dc.relation.granthttp://purl.org/au-research/grants/arc/FT130101254
dc.relation.granthttp://purl.org/au-research/grants/arc/DP150103110
dc.rights© 2020, American Society for Clinical Investigation.
dc.source.urihttps://doi.org/10.1172/jci99027
dc.subjectEndothelial Cells
dc.subjectLymphatic Vessels
dc.subjectAnimals
dc.subjectMice, Transgenic
dc.subjectHumans
dc.subjectMice
dc.subjectLymphedema
dc.subjectSyndrome
dc.subjectCadherins
dc.subjectCell Polarity
dc.subjectLymphangiogenesis
dc.subjectFemale
dc.subjectGATA2 Transcription Factor
dc.titleAtypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow
dc.typeJournal article
pubs.publication-statusPublished

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