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Unique functions for Notch4 in murine embryonic lymphangiogenesis

Ajit Muley, Minji Kim Uh, Jennifer M. James, Aino Murtomaki, Joseph D. McCarron, Chris Kitajewski, Maria Gnarra, Gloria Riitano, Yoh-suke Mukouyama, Jan Kitajewski, View ORCID ProfileCarrie J. Shawber
doi: https://doi.org/10.1101/2021.02.19.431982
Ajit Muley
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY 10032, USA
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Minji Kim Uh
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY 10032, USA
2Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA
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Jennifer M. James
3Laboratory of Stem Cell and Neuro-Vascular Biology, Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Aino Murtomaki
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY 10032, USA
4Wihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu, Helsinki, 8,00290 Finland
5Translational Cancer Medicine Program, Faculty of Medicine and Helsinki Institute of Life Science, University of Helsinki, Helsinki,, FI-00014, Finland
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Joseph D. McCarron
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY 10032, USA
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Chris Kitajewski
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY 10032, USA
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Maria Gnarra
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY 10032, USA
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Gloria Riitano
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY 10032, USA
6Departments of Molecular Medicine and Experimental Medicine, Sapienza University, Rome, 00185, Italy
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Yoh-suke Mukouyama
3Laboratory of Stem Cell and Neuro-Vascular Biology, Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Jan Kitajewski
7Department of Physiology and Biophysics, University of Illinois Chicago, Chicago, IL 60612, USA
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Carrie J. Shawber
1Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY 10032, USA
8Department of Surgery, Columbia University Medical Center, New York, NY 10032, USA
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  • ORCID record for Carrie J. Shawber
  • For correspondence: cjs2002@cumc.columbia.edu
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Abstract

In mice, embryonic dermal lymphatic development is a well-understood system used to study the role of genes in physiological lymphangiogenesis. The Notch signaling is an evolutionary conserved pathway that modulates cell fate decisions and shown to both inhibit and promote dermal lymphangiogenesis. Here, we demonstrate distinct roles for Notch4 signaling versus canonical Notch signaling in embryonic dermal lymphangiogenesis. At E14.5, actively growing dermal lymphatics expressed NOTCH1, NOTCH4 and DLL4, with DLL4 expression strongest and Notch active in the lymphangiogenic sprouts. Treatment of cultured LECs with VEGF-A or VEGF-C upregulated Dll4 transcripts, but differentially regulated Notch1 and Notch4 expression, and the Notch effectors of the Hes/Hey families, suggesting that VEGF-A and VEGF-C distinctly modulate Dll4/Notch signaling in the lymphatic endothelium. Mice nullizygous for Notch4 had an increase in the closure of the lymphangiogenic fronts towards the midline which correlated with reduced vessel caliber in the maturing lymphatic plexus. Activation of Notch4 suppressed lymphatic endothelial cell migration in a wounding assay significantly more then Notch1 activation, suggesting a dominant role for Notch4 in LEC migration. Unlike Notch4 nulls, inhibition of canonical Notch signaling by ectopically expressing a dominant negative form of MAML1 (DNMAML) in Prox1+ lymphatic endothelium suppressed lymphatic endothelial cell proliferation consistent with what has been described for the loss of lymphatic endothelial Notch1. Moreover, loss of Notch4 did not disrupt lymphatic endothelial canonical Notch signaling. Thus, we propose that Notch4 signaling and canonical Notch signaling have distinct functions in the coordination of embryonic dermal lymphangiogenesis.

Competing Interest Statement

Jan Kitajewski has received research funding from Eisai Pharmaceuticals (CU12-3625 and UICID#084028 Eisai Ltd. Research Collaborative Agreements). All other authors declare that they have no conflict of interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 20, 2021.
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Unique functions for Notch4 in murine embryonic lymphangiogenesis
Ajit Muley, Minji Kim Uh, Jennifer M. James, Aino Murtomaki, Joseph D. McCarron, Chris Kitajewski, Maria Gnarra, Gloria Riitano, Yoh-suke Mukouyama, Jan Kitajewski, Carrie J. Shawber
bioRxiv 2021.02.19.431982; doi: https://doi.org/10.1101/2021.02.19.431982
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Unique functions for Notch4 in murine embryonic lymphangiogenesis
Ajit Muley, Minji Kim Uh, Jennifer M. James, Aino Murtomaki, Joseph D. McCarron, Chris Kitajewski, Maria Gnarra, Gloria Riitano, Yoh-suke Mukouyama, Jan Kitajewski, Carrie J. Shawber
bioRxiv 2021.02.19.431982; doi: https://doi.org/10.1101/2021.02.19.431982

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