Identification of a new regulatory axis for the specification of primitive myelopoiesis and definitive hematopoiesis.

A genomic variant in the human [androgen-dependent tissue factor (TF) pathway inhibitor (TFPI) regulating protein] gene increases the risk of coronary artery disease, the leading cause of death worldwide. TFPI is the TF pathway inhibitor that is involved in coagulation. Here, we report that and form a regulatory axis that specifies primitive myelopoiesis and definitive hematopoiesis, but not primitive erythropoiesis or vasculogenesis. In zebrafish, there are 2 paralogues for (, and ). Knockdown of expression inhibits the specification of hemangioblasts, as shown by decreased expression of the hemangioblast markers, , , and ; blocks primitive hematopoiesis, as shown by decreased expression of , , and ; and disrupts the specification of hematopoietic stem cells (definitive hematopoiesis), as shown by decreased expression of and However, knockdown does not affect erythropoiesis during primitive hematopoiesis (no effect on or ) or vasculogenesis (no effect on , , , or ). Knockdown of expression does not have apparent effects on all markers tested. Knockdown of reduced the expression of , and hematopoietic defects in morphants were rescued by overexpression. These data suggest that the regulation of expression is one potential mechanism by which regulates primitive myelopoiesis and definitive hematopoiesis.-Wang, L., Wang, X., Wang, L., Yousaf, M., Li, J., Zuo, M., Yang, Z., Gou, D., Bao, B., Li, L., Xiang, N., Jia, H., Xu, C., Chen, Q., Wang, Q. K. Identification of a new regulatory axis for the specification of primitive myelopoiesis and definitive hematopoiesis.