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Senior Scientist
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Chronic Disease
, Ottawa Hospital Research Institute
Professor, Department of Obstetrics and Gynaecology, University of Ottawa
Professor, Department of Biochemistry, Microbiology and Immunology (BMI), University of Ottawa
Research Interests
I. Asymmetric cell division and cancers
In cell division, duplicated chromosomes are assembled into a structure called the spindle, which separates the chromosomes into equal halves for each daughter cells; the process of chromosome separation is called anaphase. To complete cell division, the cell itself also needs to be divided, by a structure called the cytokinetic contractile ring; this process is called cytokinese. These two processes must be coordinated both temporally (anaphase before cytokinesis) and spatially (such that each daughter cell receives one set of chromosomes). Defects in anaphase, cytokinesis, or their coordination result in chromosome aneuploidy (containing an abnormal number of chromosomes), which is a major cause of human cancers.
Cells can divide symmetrically or asymmetrically. Anaphase-cytokinesis coordination is well understood in symmetric cell division, in which a mother cell splits into two identical daughter cells. However, in asymmetric cell division, in which the two daughters receive identical chromosomes but different non-chromosomal materials, the coordination between anaphase and cytokinesis is more complex and poorly understood.
We are studying this problem in an extreme form of asymmetric cell division: egg maturation - in which half of the chromosomes are discarded with minimum cell contents in a diminutive cell called polar body and the other half are retained by the robust egg. Critical to polar body emission is the attachment of one spindle pole to the oocyte cortex prior to anaphase. We have found that asymmetric spindle pole attachment and anaphase initiation are required for localized cortical activation of an enzyme called Cdc42, which in turn defines the surface of the impending polar body. The Cdc42 activity zone is circumscribed by a RhoA-based actomyosin contractile ring. During cytokinesis, constriction of the RhoA contractile ring is accompanied by Cdc42-mediated membrane outpocketing such that one spindle pole and one set of chromosomes are pulled into the Cdc42 enclosure. Polar body emission thus not only requires a classical RhoA contractile ring, but also a Cdc42-mediated membrane protrusion.
Current theory of cancer origin focuses on cancer stem cells, thought to be the "seeds" of all cancers. Like all stem cells, cancer stem cells undergo asymmetric cell division: one daughter remains a stem cell but the other undergoes rapid proliferation (symmetric cell division) to produce the bulk of the cancer mass. Current chemotherapy is thought to induce cancer remission by destroying only these rapidly dividing cancer cells but not eliminating cancer stem cells. Therefore many patients experience cancer comeback following a period of remission. Our hope is to find new therapeutic strategies that eliminate cancer stem cells by targeting the cellular machinery responsible for asymmetric cell division.
II. Infertility and Birth Defects
One of the most intriguing facts about vertebrate reproduction is that females start to produce primordial oocytes (eggs) during embryonic life and cease production shortly after birth. This means that in humans, women draw on their "at birth egg reserve" for their entire reproductive life until menopause! Perhaps due to this unusual egg "longevity", human eggs have a very high rate of chromosome aneuploidy, particularly eggs in women of advanced reproductive ages. Chromosome aneuploidy, the single most important factor in infertility and birth defects, is exacerbated with increasing maternal age. For example, at maternal age 20 to 24, the probability of carrying a Down Syndrome (Trisomy 21 or "three copies of chromosome 21") fetus is one in 1562; at age 35 to 39 the probability is one in 214, and above age 45 the probability is one in 19! [Huether, C.A. (1998)]. "Maternal age specific risk rate estimates for Down syndrome among live births in whites and other races from Ohio and metropolitan Atlanta, 1970-1989". J Med Genet 35(6): 482-490]. Aneuploidy with most other chromosomes has even more severe consequences, resulting in fetal death (miscarriages) or death of the conceptus before clinical definition of pregnancy is reached.
We have been studying oocyte maturation using the amphibian Xenopus laevis as a vertebrate model organism for the many experimental advantages over mammalian species. We have discovered that the amphibian oocytes produced massive amounts of an enzyme called ornithine decarboxylase (ODC) during maturation. ODC breaks down ornithine (an amino acid) to putrescine, an essential cell metabolite whose exact function remains unclear. We found that when ODC production was inhibited, the eggs exhibited sign of apoptosis (programmed cell death) and the resultant embryos were fragmented, a telltale sigh of severe chromosome aneuploidy. We are investigating the role of ODC in oocyte maturation in mammals, using the mouse model. Our specific goals are to 1) establish a physiological role for ODC in mouse oocyte maturation and 2) to understand the biochemical mechanism by which ODC preserves oocyte health. Pending ethics approval, we will also confirm our key findings using human oocytes (immature oocytes deemed not suitable for in vitro fertilization) donated by consenting patients at the Ottawa Fertility Center. Our long-term goal is to understand the molecular basis, and potential intervention, of increased aneuploidy in women of advanced reproductive age.
Major Awards
Premier's Research Excellence Award (PREA) (2000-2005)
Medical Research Council (now CIHR) Scholarship (1995-2000)
Grants (current)
Canadian Institute of Health Research (CIHR)
CIHR-National Natural Science Foundation (China) joint research grant
Natural Sciences and Engineering Research Council (NSERC) of Canada
Selected Publications
Yong Zhou, Chunqi Ma, Jennifer Karmouch, Hadia Arabi Katbi, and X. Johné Liu. Antiapoptotic role for ornithine decarboxylase during oocyte maturation. Mol. Cell. Biol. 29:1786-1795 (2009)
Xuan Zhang, Chunqi Ma, Ann L. Miller, Hadia Arabi Katbi, William M Bement, and X. Johné Liu. Polar body emission requires a RhoA contractile ring and Cdc42-mediated membrane protrusion. Developmental Cell 15:386-400 (2008). (XZ and CM are equal contributing authors)
Ling Wang, Zhenbo Wang, Xuan Zhang, Greg FitzHarris, Jay M. Baltz, and X. Johné Liu. Brefeldin A disrupts asymmetric spindle positioning in mouse oocytes. Dev. Biol. 313:155-166 (2008). (LW and ZW are equal contributing authors)
Chunqi Ma, Héléne A. Benink, Daye Cheng, Ling Wang, Yanwei Xi, Pei-Pei Zheng, Véronique Montplaisir1, William M. Bement and X. Johné Liu. Cdc42 activation coordinates spindle positioning and the first polar body formation in oocyte maturation. Current Biology 16:214-220 (2006)
Xun Shawn Liu, Chunqi Ma, Al-Walid Haman and X. Johné Liu. Transcription-dependent and transcription-independent functions of the classical progesterone receptor in Xenopus ovaries. Dev. Biol. 283:180-190 (2005).
Jing Wang and X. Johné Liu. Progesterone inhibits protein kinase A (PKA) in Xenopus oocytes: demonstration of endogenous oocyte PKA activities using expressed substrate. J. Cell Sci. 117:5107-5166 (2004).
Jing Wang and X. Johné Liu. A G-protein coupled receptor kinases induces Xenopus oocyte maturation. J. Biol. Chem. 278:15809 (2003).
Chunqi Ma, Cathy Cummings, and X. Johné Liu. Bi-phasic activation of aurora-A kinase and meiosis I and meiosis II transition in Xenopus oocytes. Mol. Cell. Biol. 23:1703-1716 (2003).
Ronald A. Booth, Cathy Cummings, Mario Tiberi, and X. Johné Liu. GIPC participates in G protein signaling downstream of IGF-1 receptor. J. Biol. Chem . 277:6719-6725 (2002).
Yinglun Sheng, Mario Tiberi, Ronald A. Booth, Chunqi Ma, and X. Johné Liu. Regulation of Xenopus oocyte meiosis arrest by G protein ?? subunits. Current Biology 11:405-416 (2001).
Mustafa Bayaa, Ronald A. Booth, Yinglun Sheng, and X. Johné Liu. The classical progesterone receptor mediates Xenopus oocyte maturation through a nongenomic mechanism. Proc. Natl. Acad. Sci. USA, 97:12607-12612 (2000).
BOOK AND CHAPTERS
X. Johné Liu, as Editor, Xenopus Protocols: Cell Biology and Signal Transduction Methods in Molecular Biology vol 322 (Humana Publishing Inc). 2006.
Wang J and Liu XJ. (2006) Monitoring protein kinase A activities using expressed substrate in live cells. In Xenopus Protocols: Cell Biology and Signal Transduction. Liu XJ, ed. (a volume for the Methods in Molecular Biology series, Humana Publishing Inc). vol. 322 pp 425-434.
Liu XS and Liu XJ. (2006) Oocyte isolation and enucleation. In Xenopus Protocols: Cell Biology and Signal Transduction. Liu XJ, ed. (a volume for the Methods in Molecular Biology series, Humana Publishing Inc). volume 322, pp 31-42.
CURRENT LAB MEMBERS
Postdoctoral Fellows
Dr. Yong Tao
Dr. Hua Shao
Graduate Students
Hadia Arabi Katbi
Julie Leblanc
Geoffrey Leblond
Heather Sarazin
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