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

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  • Additional Information
    • Affiliation:
      Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
      SA Pathology, Adelaide, South Australia, Australia.
      Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
      Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
      Institute of Physiological Chemistry and Pathobiochemistry, University of Muenster, Muenster, Germany.
      Division of Genomics of Development and Disease, Institute for Molecular Bioscience, University of Queensland, Saint Lucia, Queensland, Australia.
      Organogenesis and Cancer Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
      Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia.
      Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
      Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
      Department of Developmental Biology, Washington University School of Medicine, Saint Louis, Missouri, USA.
    • Abstract:
      The 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.
    • Journal Subset:
      Biomedical; USA
    • ISSN:
      0021-9738
    • MEDLINE Info:
      PMID: NLM32182215 NLM UID: 7802877
    • Publication Date:
      In Process
    • Publication Date:
      20200610
    • DOI:
      http://dx.doi.org/10.1172/JCI99027
    • Accession Number:
      143527843
  • Citations
    • ABNT:
      BETTERMAN, K. L. et al. Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow. Journal of Clinical Investigation, [s. l.], v. 130, n. 6, p. 3315–3328, 2020. DOI 10.1172/JCI99027. Disponível em: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=rzh&AN=143527843. Acesso em: 14 ago. 2020.
    • AMA:
      Betterman KL, Sutton DL, Secker GA, et al. Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow. Journal of Clinical Investigation. 2020;130(6):3315-3328. doi:10.1172/JCI99027
    • APA:
      Betterman, K. L., Sutton, D. L., Secker, G. A., Kazenwadel, J., Oszmiana, A., Lim, L., Miura, N., Sorokin, L., Hogan, B. M., Kahn, M. L., McNeill, H., & Harvey, N. L. (2020). Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow. Journal of Clinical Investigation, 130(6), 3315–3328. https://doi.org/10.1172/JCI99027
    • Chicago/Turabian: Author-Date:
      Betterman, Kelly L., Drew L. Sutton, Genevieve A. Secker, Jan Kazenwadel, Anna Oszmiana, Lillian Lim, Naoyuki Miura, et al. 2020. “Atypical Cadherin FAT4 Orchestrates Lymphatic Endothelial Cell Polarity in Response to Flow.” Journal of Clinical Investigation 130 (6): 3315–28. doi:10.1172/JCI99027.
    • Harvard:
      Betterman, K. L. et al. (2020) ‘Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow’, Journal of Clinical Investigation, 130(6), pp. 3315–3328. doi: 10.1172/JCI99027.
    • Harvard: Australian:
      Betterman, KL, Sutton, DL, Secker, GA, Kazenwadel, J, Oszmiana, A, Lim, L, Miura, N, Sorokin, L, Hogan, BM, Kahn, ML, McNeill, H & Harvey, NL 2020, ‘Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow’, Journal of Clinical Investigation, vol. 130, no. 6, pp. 3315–3328, viewed 14 August 2020, .
    • MLA:
      Betterman, Kelly L., et al. “Atypical Cadherin FAT4 Orchestrates Lymphatic Endothelial Cell Polarity in Response to Flow.” Journal of Clinical Investigation, vol. 130, no. 6, June 2020, pp. 3315–3328. EBSCOhost, doi:10.1172/JCI99027.
    • Chicago/Turabian: Humanities:
      Betterman, Kelly L., Drew L. Sutton, Genevieve A. Secker, Jan Kazenwadel, Anna Oszmiana, Lillian Lim, Naoyuki Miura, et al. “Atypical Cadherin FAT4 Orchestrates Lymphatic Endothelial Cell Polarity in Response to Flow.” Journal of Clinical Investigation 130, no. 6 (June 2020): 3315–28. doi:10.1172/JCI99027.
    • Vancouver/ICMJE:
      Betterman KL, Sutton DL, Secker GA, Kazenwadel J, Oszmiana A, Lim L, et al. Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow. Journal of Clinical Investigation [Internet]. 2020 Jun [cited 2020 Aug 14];130(6):3315–28. Available from: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=rzh&AN=143527843