Our long-term goal is to understand how the hematopoietic system is established in the developing embryo. ER71, Fli1, Erg, Ets1, Ets2, Elk3 and Tel Ets transcription factors as well as GATA2 and Scl are relevant for hematopoietic and vascular development during embryogenesis. They are expressed in hematopoietic and endothelial cells. Moreover, mice display varying degrees of hematopoietic and vascular defects when any of these genes is inactivated. Clearly, there is an overlap in the gene regulatory network downstream of Ets, GATA2 and Scl that we need to understand. Indeed, emerging studies argue that Ets-GATA-Ebox motif is critical for hematopoietic development. For example, Runx1 expression in hematopoietic stem cells is regulated by the Ets-GATA-Ebox motif. As for Ets factors, it is not yet apparent how the Ets factor specificity is determined nor how much of the functional redundancy exists among Ets factors in hematopoietic and vascular development. We have exciting preliminary data suggesting that there is an Ets hierarchy and that ER71 is at the top. Notably, ER71 deficiency leads to the most severe hematopoietic and vascular defects compared to other Ets factors, GATA2 or Scl deficiency. Intriguingly, ER71 expression during embryogenesis is transient: it is expressed in the primitive streak and large vessels of dorsal aorta where definitive hematopoietic program is activated. In later stages yolk sac, fetal liver or bone marrow, ER71 expression is greatly reduced, but other Ets factor expression is prominent. From these data, we envision that ER71 induces Ets-GATA2-Scl triad mediated hematopoietic program activation. In this proposal, we test the following hypotheses: 1) ER71 is at the top of the hierarchy of Ets transcription factors in hematopoietic program induction;2) Ets transcription factors together with GATA2 and Scl will activate primitive and definitive hematopoietic program;3) Ets-GATA2-Scl triad is dynamic, in which Ets factors will dictate the specificity of target gene with Ets-GATA-Ebox motif and subsequent cellular fate.
Aim1 will determine the window of time that ER71 functions in hematopoietic induction.
Aim2 will establish that ER71 is at the top of Ets hierarchy and directly activates Ets gene expression.
Aim3 will determine that ER71 mediated Ets activation results in cooperative Ets-GATA2-Scl target gene activation and hematopoietic program induction. This topic is most fundamental to the developmental biology of hematopoietic and vascular fields. Successful completion of the work will lead to a deeper understanding of how hematopoietic system is established during embryogenesis. Such knowledge will also be directly applicable for pluripotent stem cell research on regenerative biology and medicine, bone marrow hematopoiesis and hematopoietic disorders.
This grant proposal is to understand how blood system is established in the developing mouse embryo. Toward this goal, we will characterize an Ets master regulator ER71 and its downstream target genes. We believe that ER71 induces other Ets genes and that these Ets genes subsequently activate hematopoietic program induction together with other master regulators GATA2 and Scl. It will be important to understand genetic program activated by these master regulators. The outcome of this study is highly relevant to basic research, regenerative medicine and blood disorders.
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