Hematopoietic and endothelial stem cells are derived from a common embryonic precursor termed the hemangioblast. The genetic cascades that regulate differentiation of the hemangioblast to hematopoietic and endothelial stem cells are largely unknown. Much of embryonic development is coordinately regulated by temporal and spatial expression of transcription factors, such as the Homeobox (Hox) gene family. We and others isolated a divergent Hox gene termed Hex (or Prh) that in the adult is preferentially expressed in all myeloid and B-cells but not T-cells. It is down-regulated during differentiation. During embryogenesis, Hex is an early marker of endothelial development, and is essential for endodermal organ development. Using in vitro Hex -/- embryonic stem (ES) cell differentiation and chimeric mice, we have found that Hex is essential for differentiation of the hemangioblast to definitive hematopoietic progenitors. We also found that forced expression of Hex in T-cells, where it is not normally expressed, inhibited thymic T-cell development, and maintained expression of myeloid markers. These data generated the underlying hypothesis of this proposal, that Hex regulates the differentiation of the hemangioblast to hematopoietic progenitor cells. This hypothesis will be tested by answering 3 specific questions: 1) What is the biochemical mechanism by which Hex induces hematopoietic development? 2) Where does Hex fit in the hierarchy of transcription factors and cytokines that are essential for hematopoietic development? 3) What is the spatial and temporal location of Hex's function in the differentiation of the hemangioblast during embryogenesis? Answering these questions will elucidate the mechanism by which Hex regulates the formation of the first hematopoietic cells, and will place it in a spatial, temporal and transcriptional context within the developing embryo. It will also provide novel insight into the molecular regulation of embryonic hematopoiesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075783-02
Application #
6908129
Study Section
Special Emphasis Panel (ZRG1-HEME-B (03))
Program Officer
Thomas, John
Project Start
2004-07-01
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$337,500
Indirect Cost
Name
University of New Mexico
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Williamson, Elizabeth A; Boyle, Timothy J; Raymond, Rebecca et al. (2012) Cytotoxic activity of the titanium alkoxide (OPy)(2)Ti(4AP)(2) against cancer colony forming cells. Invest New Drugs 30:114-20
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Williamson, Elizabeth A; Damiani, Leah; Leitao, Andrei et al. (2012) Targeting the transposase domain of the DNA repair component Metnase to enhance chemotherapy. Cancer Res 72:6200-8
Fnu, Sheema; Williamson, Elizabeth A; De Haro, Leyma P et al. (2011) Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining. Proc Natl Acad Sci U S A 108:540-5
Allen, Chris; Ashley, Amanda K; Hromas, Robert et al. (2011) More forks on the road to replication stress recovery. J Mol Cell Biol 3:4-12
Ponder, Jessica; Yoo, Byong Hoon; Abraham, Adedoyin D et al. (2011) Neoamphimedine circumvents metnase-enhanced DNA topoisomerase II? activity through ATP-competitive inhibition. Mar Drugs 9:2397-408
Wiggins, Charles L; Harlan, Linda C; Nelson, Harold E et al. (2010) Age disparity in the dissemination of imatinib for treating chronic myeloid leukemia. Am J Med 123:764.e1-9
Kong, Kimi Y; Williamson, Elizabeth A; Rogers, Jason H et al. (2009) Expression of Scl in mesoderm rescues hematopoiesis in the absence of Oct-4. Blood 114:60-3
Wray, Justin; Williamson, Elizabeth A; Sheema, Sheema et al. (2009) Metnase mediates chromosome decatenation in acute leukemia cells. Blood 114:1852-8
Williamson, Elizabeth A; Rasila, Kanwaldeep Kaur; Corwin, Lori Kwan et al. (2008) The SET and transposase domain protein Metnase enhances chromosome decatenation: regulation by automethylation. Nucleic Acids Res 36:5822-31

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