TY - JOUR
T1 - VE-cadherin endocytosis controls vascular integrity and patterning during development
AU - Grimsley-Myers, Cynthia M.
AU - Isaacson, Robin H.
AU - Cadwell, Chantel M.
AU - Campos, Jazmin
AU - Hernandes, Marina S.
AU - Myers, Kenneth R.
AU - Seo, Tadahiko
AU - Giang, William
AU - Griendling, Kathy K.
AU - Kowalczyk, Andrew P.
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (R01AR050501 and R01AR048266 to A.P. Kowalczyk and HL095070 to K.K. Griendling). This research project was supported in part by the Emory University Integrated Cellular Imaging Microscopy Core of the Winship Cancer Institute comprehensive cancer center grant, P30CA138292. This study was supported in part by the Mouse Transgenic and Gene Targeting Core and the Emory Integrated Genomics Core, which are subsidized by the School of Medicine, Emory University, and are Emory Integrated Core Facilities. Additional support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. The authors declare no competing financial interests.
Publisher Copyright:
© 2020 Grimsley-Myers et al.
PY - 2020/5/4
Y1 - 2020/5/4
N2 - Tissue morphogenesis requires dynamic intercellular contacts that are subsequently stabilized as tissues mature. The mechanisms governing these competing adhesive properties are not fully understood. Using gain- and loss-of-function approaches, we tested the role of p120-catenin (p120) and VE-cadherin (VE-cad) endocytosis in vascular development using mouse mutants that exhibit increased (VE-cadGGG/GGG) or decreased (VE-cadDEE/DEE) internalization. VE-cadGGG/GGG mutant mice exhibited reduced VE-cad-p120 binding, reduced VE-cad levels, microvascular hemorrhaging, and decreased survival. By contrast, VE-cadDEE/DEE mutants exhibited normal vascular permeability but displayed microvascular patterning defects. Interestingly, VE-cadDEE/DEE mutant mice did not require endothelial p120, demonstrating that p120 is dispensable in the context of a stabilized cadherin. In vitro, VE-cadDEE mutant cells displayed defects in polarization and cell migration that were rescued by uncoupling VE-cadDEE from actin. These results indicate that cadherin endocytosis coordinates cell polarity and migration cues through actin remodeling. Collectively, our results indicate that regulated cadherin endocytosis is essential for both dynamic cell movements and establishment of stable tissue architecture.
AB - Tissue morphogenesis requires dynamic intercellular contacts that are subsequently stabilized as tissues mature. The mechanisms governing these competing adhesive properties are not fully understood. Using gain- and loss-of-function approaches, we tested the role of p120-catenin (p120) and VE-cadherin (VE-cad) endocytosis in vascular development using mouse mutants that exhibit increased (VE-cadGGG/GGG) or decreased (VE-cadDEE/DEE) internalization. VE-cadGGG/GGG mutant mice exhibited reduced VE-cad-p120 binding, reduced VE-cad levels, microvascular hemorrhaging, and decreased survival. By contrast, VE-cadDEE/DEE mutants exhibited normal vascular permeability but displayed microvascular patterning defects. Interestingly, VE-cadDEE/DEE mutant mice did not require endothelial p120, demonstrating that p120 is dispensable in the context of a stabilized cadherin. In vitro, VE-cadDEE mutant cells displayed defects in polarization and cell migration that were rescued by uncoupling VE-cadDEE from actin. These results indicate that cadherin endocytosis coordinates cell polarity and migration cues through actin remodeling. Collectively, our results indicate that regulated cadherin endocytosis is essential for both dynamic cell movements and establishment of stable tissue architecture.
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U2 - 10.1083/jcb.201909081
DO - 10.1083/jcb.201909081
M3 - Article
C2 - 32232465
AN - SCOPUS:85082792223
SN - 0021-9525
VL - 219
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 5
M1 - e201909081
ER -