Organisms that reproduce sexually utilize a specialized cell division program called meiosis to reduce their chromosome number by half to generate haploid gametes. Proper execution of this process is crucial, since errors in meiotic chromosome segregation result in aneuploidy, the leading known cause of miscarriages and birth defects in humans. Chromosome segregation in female meiotic cells (oocytes) is highly error prone; defects in this process account for most of the aneuploidy found in human embryos. However, surprisingly little is known about the mechanisms that act to segregate chromosomes in oocytes, or the reasons why these mechanisms are so susceptible to error. Oocytes have some special features that necessitate the use of novel cell division mechanisms. Perhaps most significantly, oocytes lack centrosomes, which define and organize the spindle poles in other cell types; therefore spindles in these cells are morphologically distinct. Using C. elegans as a model, we previously found that acentrosomal oocyte spindles have a surprising organization; chromosomes are ensheathed by microtubule bundles that run along their sides, making lateral contacts, instead of forming end-on attachments. Moreover, we also defined new mechanisms that facilitate chromosome congression and segregation on these spindles, driven by motor-driven movement along these lateral bundles. These mechanisms are distinct from other cell types, where end-on attachment of microtubules to kinetochores is the primary driver of chromosome movement. Therefore, our work has revealed a new strategy utilized by C. elegans oocytes for controlling chromosome dynamics during cell division. Building on these discoveries, the proposed studies will now extend this work to determine if these mechanisms facilitate chromosome congression and segregation in mammalian oocytes as well. The work will be performed using mouse as a model, and will include two major aims: 1) Defining the organization of the mammalian oocyte spindle. We will use super-resolution imaging to define the organization of the mouse oocyte spindle, defining microtubule contacts during the meiotic divisions and assessing the localization of key components. 2) Probing kinetochore-independent mechanisms in mammalian oocytes. We will assess the consequences of preventing kinetochore attachments and we will perform functional studies to reveal molecular mechanisms driving kinetochore-independent chromosome movements. Altogether, this work will reveal mechanisms by which chromosomes align and segregate during oocyte meiosis, and will lend insight into an important yet poorly understood cell division. These studies may provide information about how meiotic segregation errors arise, contributing to our understanding of the etiology of Down Syndrome and other birth defects.
|Effective start/end date||6/1/16 → 1/31/19|
- March of Dimes Foundation (1-FY16-240)
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