Investigating the role of transcription factor nfe2l2 in vascular and hematopoietic stem and progenitor cell development

One of the most essential types of cells in humans, as well as many other organisms, are hematopoietic stem cells (HSCs). These cells serve as the precursors to all other types of blood and immune cells in the body, including red blood cells and myeloid and lymphoid immune cells. Nfe2l2a is a key regulator of genes involved in the antioxidant response that is triggered by high levels of ROS in the body. The role nfe2l2a plays in HSC development is not fully understood, but previous research suggested that ROS produced as a byproduct of glucose metabolism are required for normal development of HSCs in zebrafish embryos. To increase our understanding of the role of ROS-mediated signaling in HSC development, my research investigated the role of transcription factor nfe2l2a in vascular development and embryonic HSPC specification using the embryonic zebrafish as a model system. My work found that knockdown of nfe2l2a via morpholino injection resulted in a reduction in HSPCs, suggesting nfe2l2a is required for HSPC specification. While investigating how nfe2l2a regulates HSC specification, I found that nfe2l2a knockdown caused reduced expression of various arterial and venous markers and apparent arterial-venous malformations. To gain a more holistic understanding of the role nfe2l2a plays as an upstream regulator of many antioxidant response genes, I also examined the expression of hematopoietic and vascular marker genes in embryos where the nfe2l2a target gene prdx1 was knocked down by morpholino injection. Overall, I show that nfe2l2a is required for normal vascular development and HSPC specification. I additionally show that Nfe2l2a regulates the expression of prdx1 in vascular and hemogenic mesoderm and that Nfe2l2a likely controls vascular and HSPC development through control of prdx1 expression