TY - JOUR
T1 - Notch activation is required for downregulation of HoxA3-dependent endothelial cell phenotype during blood formation
AU - Sanghez, Valentina
AU - Luzzi, Anna
AU - Clarke, Don
AU - Kee, Dustin
AU - Beuder, Steven
AU - Rux, Danielle
AU - Osawa, Mitsujiro
AU - Madrenas, Joaquín
AU - Chou, Tsui Fen
AU - Kyba, Michael
AU - Iacovino, Michelina
N1 - Publisher Copyright:
© 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.
PY - 2017/10
Y1 - 2017/10
N2 - 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 downre-gulate endothelial markers during EHT.
AB - 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 downre-gulate endothelial markers during EHT.
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U2 - 10.1371/journal.pone.0186818
DO - 10.1371/journal.pone.0186818
M3 - Article
C2 - 29073173
AN - SCOPUS:85032451223
SN - 1932-6203
VL - 12
JO - PloS one
JF - PloS one
IS - 10
M1 - e0186818
ER -