Notch activation is required for downregulation of HoxA3-dependent endothelial cell phenotype during blood formation
Abstract
Hemogenic endothelium (HE) undergoes endothelial-to-hematopoietic transition (EHT) to generate blood, a process that requires progressive down-regulation of endothelial genes and induction of hematopoietic ones. Previously, we have shown that the transcription factor HoxA3 prevents blood formation by inhibiting Runx1 expression, maintaining endothelial gene expression and thus blocking EHT. In the present study, we show that HoxA3 also prevents blood formation by inhibiting Notch pathway. HoxA3 induced upregulation of Jag1 ligand in endothelial cells, which led to cis-inhibition of the Notch pathway, rendering the HE nonresponsive to Notch signals. While Notch activation alone was insufficient to promote blood formation in the presence of HoxA3, activation of Notch or downregulation of Jag1 resulted in a loss of the endothelial phenotype which is a prerequisite for EHT. Taken together, these results demonstrate that Notch pathway activation is necessary to downregulate endothelial markers during EHT.
Additional Information
© 2017 Sanghez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: June 9, 2017; Accepted: October 9, 2017; Published: October 26, 2017. We thank Dr. Michael Bevan for the OP9-Dll1 cells. This research was supported by NIH grants U01 HL100407 and 1R01 HL081186 and by the American Heart Association grant 12SDG9260007. J.M. holds a Tier I Canada Research Chair ih Human Immunology. Author Contributions: Conceptualization: Valentina Sanghez, Michelina Iacovino. Data curation: Valentina Sanghez, Anna Luzzi, Don Clarke, Dustin Kee, Steven Beuder, Danielle Rux, Mitsujiro Osawa, Tsui-Fen Chou. Formal analysis: Valentina Sanghez, Tsui-Fen Chou, Michelina Iacovino. Writing ± original draft: Valentina Sanghez, Michelina Iacovino. Writing ± review & editing: Don Clarke, Joaquin Madrenas, Michael Kyba. The authors have declared that no competing interests exist.Attached Files
Published - pone.0186818.pdf
Supplemental Material - pone.0186818.s001.pdf
Supplemental Material - pone.0186818.s002.pdf
Supplemental Material - pone.0186818.s003.pdf
Supplemental Material - pone.0186818.s004.pdf
Supplemental Material - pone.0186818.s005.pdf
Supplemental Material - pone.0186818.s006.pdf
Supplemental Material - pone.0186818.s007.pdf
Supplemental Material - pone.0186818.s008.pdf
Supplemental Material - pone.0186818.s009.pdf
Supplemental Material - pone.0186818.s010.pdf
Supplemental Material - pone.0186818.s011.pdf
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Additional details
- PMCID
- PMC5658089
- Eprint ID
- 114032
- Resolver ID
- CaltechAUTHORS:20220323-565416000
- HL100407
- NIH
- HL081186
- NIH
- 12SDG9260007
- American Heart Association
- Canada Research Chairs Program
- Created
-
2022-03-25Created from EPrint's datestamp field
- Updated
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2022-03-25Created from EPrint's last_modified field