Open AccessNotch activation is required for downregulation of HoxA3-dependent endothelial cell phenotype during blood formation
Author(s) -
Valentina Sanghez,
Anna Luzzi,
Don Clarke,
Dustin Kee,
Steven Beuder,
Danielle Rux,
Mitsujiro Osawa,
Joaquı́n Madrenas,
Tsui Fen Chou,
Michael Kyba,
Michelina Iacovino
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0186818
Subject(s) - downregulation and upregulation , notch signaling pathway , jag1 , runx1 , microbiology and biotechnology , endothelium , haematopoiesis , transcription factor , biology , chemistry , signal transduction , stem cell , gene , genetics
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.