Notch activation is required for downregulation of HoxA3-dependent endothelial cell phenotype during blood formation

Valentina Sanghez, Anna Luzzi, Don Clarke, Dustin Kee, Steven Beuder, Danielle Rux, Mitsujiro Osawa, Joaquín Madrenas, Tsui Fen Chou, Michael Kyba, Michelina Iacovino

Research output: Contribution to journalArticlepeer-review

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 downre-gulate endothelial markers during EHT.

Original languageEnglish (US)
Article numbere0186818
JournalPloS one
Volume12
Issue number10
DOIs
StatePublished - Oct 2017

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