TY - JOUR
T1 - Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow
AU - Betterman, Kelly L.
AU - Sutton, Drew L.
AU - Secker, Genevieve A.
AU - Kazenwadel, Jan
AU - Oszmiana, Anna
AU - Lim, Lillian
AU - Miura, Naoyuki
AU - Sorokin, Lydia
AU - Hogan, Benjamin M.
AU - Kahn, Mark L.
AU - McNeill, Helen
AU - Harvey, Natasha L.
N1 - Funding Information:
We thank Chris Brown and staff at the SA Pathology Animal Facility and UniSA Core Animal Facility for animal husbandry. This study used the services of the Australian Phenomics Network Histopathology and Organ Pathology Service (University of Melbourne, Parkville, Australia) and the SAHMRI Histology Slide Scanning Service (Adelaide, Australia). Confocal microscopy and flow cytometry were performed at the Detmold Imaging and Flow Cytometry Facility (UniSA and SA Pathology, Adelaide, Australia). This work was supported by grants from the NHMRC (APP1061365 and APP1146352, to NLH), the Australian Research Council (ARC) (DP150103110, to BMH and NLH), and the Hospital Research Foundation (to NLH). NLH was supported by an ARC Future Fellowship (FT130101254).
Publisher Copyright:
© 2020, American Society for Clinical Investigation.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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 GATAbinding 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.
AB - 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 GATAbinding 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.
UR - http://www.scopus.com/inward/record.url?scp=85085904006&partnerID=8YFLogxK
U2 - 10.1172/JCI99027
DO - 10.1172/JCI99027
M3 - Article
C2 - 32182215
AN - SCOPUS:85085904006
VL - 130
SP - 3315
EP - 3328
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 6
ER -