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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL063736-13
Application #
8372554
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Thomas, John
Project Start
2000-02-10
Project End
2017-05-31
Budget Start
2012-09-01
Budget End
2013-05-31
Support Year
13
Fiscal Year
2012
Total Cost
$380,000
Indirect Cost
$130,000
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Oladipupo, Sunday S; Smith, Craig; Santeford, Andrea et al. (2014) Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis. Proc Natl Acad Sci U S A 111:13379-84
Liu, Fang; Kang, Inyoung; Park, Changwon et al. (2012) ER71 specifies Flk-1+ hemangiogenic mesoderm by inhibiting cardiac mesoderm and Wnt signaling. Blood 119:3295-305
Ma, Yunglin D; Park, Changwon; Zhao, Haibo et al. (2009) Defects in osteoblast function but no changes in long-term repopulating potential of hematopoietic stem cells in a mouse chronic inflammatory arthritis model. Blood 114:4402-10
Lugus, Jesse J; Park, Changwon; Ma, Yunglin D et al. (2009) Both primitive and definitive blood cells are derived from Flk-1+ mesoderm. Blood 113:563-6
Lee, Dongjun; Park, Changwon; Lee, Ho et al. (2008) ER71 acts downstream of BMP, Notch, and Wnt signaling in blood and vessel progenitor specification. Cell Stem Cell 2:497-507
Ma, Yunglin D; Lugus, Jesse J; Park, Changwon et al. (2008) Differentiation of mouse embryonic stem cells into blood. Curr Protoc Stem Cell Biol Chapter 1:Unit 1F.4
Lugus, Jesse J; Chung, Yun Shin; Mills, Jason C et al. (2007) GATA2 functions at multiple steps in hemangioblast development and differentiation. Development 134:393-405
Park, Changwon; Lavine, Kory; Mishina, Yuji et al. (2006) Bone morphogenetic protein receptor 1A signaling is dispensable for hematopoietic development but essential for vessel and atrioventricular endocardial cushion formation. Development 133:3473-84
Lugus, Jesse J; Park, Changwon; Choi, Kyunghee (2005) Developmental relationship between hematopoietic and endothelial cells. Immunol Res 32:57-74
Zhang, Wen Jie; Park, Changwon; Arentson, Elizabeth et al. (2005) Modulation of hematopoietic and endothelial cell differentiation from mouse embryonic stem cells by different culture conditions. Blood 105:111-4

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