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RhoA GTPase Controls Cytokinesis and Programmed Necrosis of Hematopoietic Progenitors

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2013, PhD, University of Cincinnati, Medicine: Molecular and Developmental Biology.
In this thesis work, the function of RhoA GTPase in regulating hematopoiesis and hematopoietic stem cells (HSCs) was defined using a conditional knockout mouse model. We demonstrated that RhoA was critical for multi-lineage differentiation in the hematopoietic system and that the deletion of RhoA resulted in hematopoietic failure and rapid lethality. Through congenic and reverse transplantation experiments, we determined that RhoA expressed within the hematopoietic lineages was essential for hematopoiesis. In the primitive HSC and progenitor (HSPC) compartment, RhoA was essential for the generation and survival of progenitor cells, but surprisingly dispensable for long-term maintenance of the HSC population. With a gene expression analysis and a RhoA add-back rescue experiment, we showed that RhoA null HSCs maintained a multi-lineage differentiation potential. Consistent with studies in other tissues, we observed a major cytokinesis block after telophase, which may reflect the defects in the final abscission of two daughter cells. Furthermore, by overexpressing effector binding mutants of RhoA, we indicated that RhoA-ROCK and RhoA-mDia interactions were critical for HSPC cytokinesis. During our cytokinesis investigations, we observed a reduction of myosin signaling, the driving force of the cell separating process. However, actin polymerization, a process integral to cell division, was not reduced by RhoA deficiency. Another interesting aspect of this study is that RhoA deficiency led to an increase in programmed necrosis, rather than apoptosis or autophagy. This increase of necrosis was observed specifically in the committed progenitor population, coinciding with the loss of progenitors in the competitive transplant experiment. This study provides conclusive evidence for the function of RhoA in the primitive hematopoietic compartment and also offers several novel insights for future studies.
Yi Zheng, Ph.D. (Committee Chair)
Hartmut Geiger, Ph.D. (Committee Member)
Gang Huang, Ph.D. (Committee Member)
Jose Cancelas-Perez, M.D. (Committee Member)
James Mulloy, Ph.D. (Committee Member)
109 p.

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Citations

  • Zhou, X. (2013). RhoA GTPase Controls Cytokinesis and Programmed Necrosis of Hematopoietic Progenitors [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1378197381

    APA Style (7th edition)

  • Zhou, Xuan. RhoA GTPase Controls Cytokinesis and Programmed Necrosis of Hematopoietic Progenitors. 2013. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1378197381.

    MLA Style (8th edition)

  • Zhou, Xuan. "RhoA GTPase Controls Cytokinesis and Programmed Necrosis of Hematopoietic Progenitors." Doctoral dissertation, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1378197381

    Chicago Manual of Style (17th edition)