PUBLICATION
EHD2 modulates Dll4 endocytosis during blood vessel development
- Authors
- Webb, A.M., Francis, C.R., Judson, R.J., Kincross, H., Lundy, K.M., Westhoff, D.E., Meadows, S.M., Kushner, E.J.
- ID
- ZDB-PUB-211129-29
- Date
- 2021
- Source
- Microcirculation (New York, N.Y. : 1994) 29(1): e12740 (Journal)
- Registered Authors
- Keywords
- Angiogenesis, Delta-like 4 protein, EHD2, Notch, Zebrafish, blood vessel development, endocytosis, trafficking, transcytosis
- MeSH Terms
- none
- PubMed
- 34820962 Full text @ Microcirculation
Citation
Webb, A.M., Francis, C.R., Judson, R.J., Kincross, H., Lundy, K.M., Westhoff, D.E., Meadows, S.M., Kushner, E.J. (2021) EHD2 modulates Dll4 endocytosis during blood vessel development. Microcirculation (New York, N.Y. : 1994). 29(1):e12740.
Abstract
Objective Despite the absolute requirement of Delta/Notch signaling to activate lateral inhibition during early blood vessel development, many mechanisms remain unclear about how this system is regulated. Our objective was to determine the involvement of Epsin 15 Homology Domain Containing 2 (EHD2) in delta-like ligand 4 (Dll4) endocytosis during Notch activation.
Approach and results Using both in vivo and in vitro models, we demonstrate that EHD2 is a novel modulator of Notch activation in endothelial cells through controlling endocytosis of Dll4. In vitro, EHD2 localized to plasma membrane bound Dll4 and caveolae. Chemical disruption of caveolae complexes resulted in EHD2 failing to organize around Dll4 as well as loss of Dll4 internalization. Reduced Dll4 internalization blunted Notch activation in endothelial cells. In vivo, EHD2 is primarily expressed in the vasculature, colocalizing with junctional marker VE-cadherin and Dll4. Knockout of EHD2 in zebrafish produced a significant increase in dysmorphic sprouts in zebrafish intersomitic vessels during development and a reduction in downstream Notch signaling.
Conclusions Overall, we demonstrate that EHD2 is necessary for Dll4 transcytosis and downstream Notch activation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping