Date of Award

5-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Cancer and Developmental Biology

Research Advisor

Brian P. Sorrentino, M.D.

Committee

John V. Cox, Ph.D. Peter J. McKinnon, Ph.D. Joseph T. Opferman, Ph.D. Derek A. Persons, M.D., Ph.D.

Keywords

apoptosis, blood, hematopoiesis, Hemgn, knockout, stem cell

Abstract

Mouse Hemogen (Hemgn) is regarded as a homologue of human Erythroid Differentiation Associated Gene (EDAG). EDAG overexpression has been postulated for association with some leukemia cases. Meanwhile, Hemgn has been found to contribute to Hoxb4 mediated hematopoietic stem cell expansion. Based on these postulations and evidences, a Hemgn knockout mouse model has been generated to study its function in normal and stress hematopoiesis. I confirmed the Hemgn expression in hematopoietic organs including bone marrow and spleen, as well as round spematids in testis. Hemgn is expressed in mouse hematopoietic stem cells and erythroid progenitor cells. Moreover, Hemgn was also found in basophilic, polychromatic and orthochromatic erythroblast cells and megakaryocytes, but absent in mature red blood cells and other differentiated blood cells. Hemgn knockout animals showed normal steady state and stress hematopoiesis and erythropoiesis. However, upon transplantation, a slight defect in lymphoid reconstitution was observed. By generating a deletion mutant of the predicted nuclear localization signal, I conclude the amino acids 61 to 78 is a functional nuclear localization signal. Both the nuclear localization signal and the predicted coiled-coil domain were required for Hemgn to protect Ba/F3 cells from IL-3 withdrawal induced apoptosis. However, the same anti-apoptotic effect of Hemgn was not seen in the myeloid 32D cell line, indicating it may require specific cell context. In conclusion, Hemgn may be an anti-apoptotic protein and may be involved in lymphoid development.

DOI

10.21007/etd.cghs.2013.0105

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