Sanghez Valentina, Luzzi Anna, Clarke Don, Kee Dustin, Beuder Steven, Rux Danielle, Osawa Mitsujiro, Madrenas Joaquín, Chou Tsui-Fen, Kyba Michael, Iacovino Michelina
Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, United States of America.
Los Angeles Biomedical Research Institute, Torrance, CA, United States of America.
PLoS One. 2017 Oct 26;12(10):e0186818. doi: 10.1371/journal.pone.0186818. eCollection 2017.
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.
造血内皮（HE）经历内皮向造血转变（EHT）以生成血液，这一过程需要逐步下调内皮基因并诱导造血基因。此前，我们已经表明转录因子HoxA3通过抑制Runx1表达、维持内皮基因表达从而阻断EHT来阻止血液形成。在本研究中，我们表明HoxA3还通过抑制Notch信号通路来阻止血液形成。HoxA3在内皮细胞中诱导Jag1配体上调，这导致Notch信号通路的顺式抑制，使HE对Notch信号无反应。虽然在存在HoxA3的情况下单独激活Notch不足以促进血液形成，但激活Notch或下调Jag1会导致内皮表型丧失，而内皮表型丧失是EHT的一个先决条件。综上所述，这些结果表明Notch信号通路激活对于在EHT期间下调内皮标志物是必要的。
