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 cytokinesis. 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, Miscarriages and Birth Defects

Women experience diminished fertility, increased risk of miscarriages and congenital birth defects in their late 30s and early 40s, 10-15 years before reaching menopause.  Egg aneuploidy (having an incorrect number of chromosomes) is the most important etiology for these reproductive problems in premenopausal women.  Aneuploid eggs result in aneuploid conceptions, most of which are lost either prior to clinical recognition of pregnancies or by miscarriages.  The small proportion that survive inevitably carry major birth defects (e.g. Down syndrome).  Accurate egg aneuploidy rates in the general population are not known, but numerous analyses of IVF samples have suggested staggeringly high rates, from 20% to virtually 100%, depending on the women’s ages.

This unusually high egg aneuploidy rate in humans is likely due to a combination of our longevity and the peculiar oogenesis (the process of generating eggs) in all vertebrates including humans.  Unlike vertebrate males that continuously generate mature sperm from germ line stem cells through adulthood, in vertebrate females oogenesis begins during the embryonic stage when germ line stem cells initiate meiosis and develop into primary oocytes.  By birth, the females have developed a finite number of primary oocytes arrested in meiotic prophase that comprises their lifetime egg supply.  A prophase oocyte contains chromosome “bivalents” each consisting of four chromatids “glued” together in the fetal ovaries.  During ovulation and fertilization in sexually mature females, the four chromatids undergo stepwise segregation to produce a haploid egg.  As females age, chromosome “glue” becomes progressively weakened, predisposing the oocytes to greater risk of chromosome segregation errors during ovulation (to a lesser degree, during fertilization), resulting in aneuploid eggs.

Given the great time lapse, it seems daunting that any measure can be found to keep these primary oocytes “fresh” while women age.  We are tackling this problem by focusing on mechanisms of chromosome segregation during oocyte maturation, concurrent with ovulation.  These efforts have yielded a possible remedy for reducing the risk of aneuploid conceptions.  It has been known for more than four decades that during mammalian estrous cycles, luteinizing hormone stimulates a transitory rise in the ovaries of ornithine decarboxylase (ODC) activity and its enzymatic product putrescine, concurrent with oocyte maturation in vivo.  Inhibition of this transitory ODC/putrescine rise, however, does not appear to affect ovulation.  Using several mouse models and combining in vitro and in vivo approaches, we demonstrated that deficiency of ODC during oocyte maturation is correlated with increased levels of egg aneuploidies.  These results suggest that the transitory ovarian ODC rise in late proestrus is important for ensuring proper chromosome segregation during oocyte maturation.  Older mice (8 months of age) exhibited about 1/3 that of young mice in LH-stimulated ovarian ODC activity and a corresponding increase of egg aneuploidies.  Moreover, a combination of putrescine supplementation in mouse drinking water leading up to oocyte retrieval and in oocyte maturation medium reduced egg aneuploidies of the old mice from 12.7% to 5.3%.  Therefore, ovarian ODC deficiency might be an important etiology of maternal aging-related aneuploidies, and peri-ovulatory putrescine supplementation might reduce the risk of aneuploid conceptions in older women. Our long-term goal is to develop an aneuploidy-reduction pill for older women.