Notch1 activation in embryonic VE-cadherin populations selectively blocks hematopoietic stem cell generation and fetal liver hematopoiesis.
Center for Molecular Medicine, Maine Medical Center Research Institute
Animals, Antigens, CD, Aorta, Cadherins, Cell Differentiation, Endothelial Cells, Gene Expression Regulation, Developmental, Hematopoiesis, Hematopoietic Stem Cells, Liver, Mice, Mice, Transgenic, Proto-Oncogene Proteins, Receptor, Notch1, Receptor, Notch4, Receptors, Notch, Transcriptional Activation
Hematopoietic stem cells (HSC) are found in several independent sites embryonically. Loss-of-function studies indicated that Notch1, but not Notch2 signaling was required for HSC emergence from the aortic-gonado-mesonephros (AGM) region. We previously showed that constitutive Notch1 activation impaired primitive erythroid differentiation, but its effects on HSC emergence from the AGM region were not studied. To further define specific roles of Notch receptors, we characterized HSC in mouse embryos expressing either Notch1 intracellular domain (ICD) or Notch4ICD in VE-cadherin or SM22α expressing populations. Although embryonic Notch1 activation in VE-cadherin populations led to lethality after E13.5, earlier defects in the fetal liver were observed. Embryos were analyzed at E12.5 to assess hematopoiesis and the phenotype of developing cells in the AGM region. We found that activation of Notch1 in the endothelial compartment in VE-cadherin expressing cells resulted in the absence of intra-aortic clusters and defects in fetal liver hematopoiesis. In contrast, although Notch4 expression is regulated during fetal hematopoiesis, activation of Notch4 in VE-cadherin expressing populations did not affect HSC phenotype, although later vascular remodeling was impaired. Likewise, activation of Notch1 in SM22α positive populations had no significant effect on hematopoiesis. Our results indicate a cell type-dependent activity and distinct features of Notch1 versus Notch4 signaling and their impact on HSC generation.
Tang, Yuefeng; Bai, Hao; Urs, Sumithra; Wang, Zack; and Liaw, Lucy, "Notch1 activation in embryonic VE-cadherin populations selectively blocks hematopoietic stem cell generation and fetal liver hematopoiesis." (2013). Maine Medical Center. 2118.