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Can we alter the leading cause of miscarriages?
Two recent studies look at what happens during the production of egg cells (oocytes), which become embryos when fertilized, as 10 to 25 percent of human embryos have a problem unique to eggs, the wrong number of chromosomes. The Northwestern University studies of miscarriage and birth defects, uncovered why some embryos never get the correct amount of genetic material, while others can self-correct.
Such mistakes are the leading cause of miscarriage and birth disorders. Regrettably, the incidence of these errors rises dramatically with a woman's age. Understanding why egg cells are more prone to division mishaps is critical, given women are choosing to start families later and later in life.
The first study, published in the Journal of Cell Biology in March, 2017, reveals that oocytes use an innovative strategy to detect and prevent errors while dividing. The second study, published Sept. 26, 2017, in PLOS Genetics, finds new proteins that kick in when meiotic division is failing, helping an embryo get the correct number of chromosomes.
"Taken together, these two studies reveal how vastly different egg cells are from every other cell, and could shed new light on why the reproductive process can be so error prone. Solving this mystery would be a first step to prolonging a woman's fertile years."
Wignall researches a structure called the spindle, an elaborate football-shaped structure that physically separates chromosomes during cell division. In most cells, structures called centrosomes help organize the spindle, ensuring a precise separation chromosomes into the correct number for each newly divided cell. However, spindles in egg cells do not have centrosomes. Their "acentrosomal" process is highly understudied compared to other types of cell division, leaving unanswered questions about why it is prone to more error when dividing.
Wignall and her team discovered that not having centrosomes, two proteins in the egg cell, KLP-15 and KLP-16, are essential in dividing the cell. Knock out these two proteins, and the normal football-shaped spindle collapses into a messy round ball. But, much to researchers surprise, a back-up protein jumps in and separates the chromosomes — sending them to their proper position at either end of the cell.
Wignall: "We were surprised to find that this protein came to the rescue and worked as a backup and properly organized the spindle!"
So why do 10 to 25 percent of embryos still end up not succeeding if there is a backup oocyte mechanism in place? One theory, Wignall thinks proteins change, or maybe get depleted, as women age.
"While these basic cell mechanisms might be difficult to grasp, they directly impact female reproduction and infertility. My lab focuses on this with the hope that one day, our research can help people experiencing fertility issues at in vitro fertilization clinics."
Wignall performs her research on oocytes using the small but powerful research organism called C. elegans — a worm. Her lab will next perform parallel studies in mice in collaboration with Teresa Woodruff, a reproductive scientist and director of the Women's Health Research Institute at Northwestern University Feinberg School of Medicine. Then her team will study these cell division mechanisms in human oocytes.
Abstract: Caenorhabditis elegans oocytes detect meiotic errors in the absence of canonical end-on kinetochore attachments
Mitotically dividing cells use a surveillance mechanism, the spindle assembly checkpoint, that monitors the attachment of spindle microtubules to kinetochores as a means of detecting errors. However, end-on kinetochore attachments have not been observed in Caenorhabditis elegans oocytes and chromosomes instead associate with lateral microtubule bundles; whether errors can be sensed in this context is not known. Here, we show that C. elegans oocytes delay key events in anaphase, including AIR-2/Aurora B relocalization to the microtubules, in response to a variety of meiotic defects, demonstrating that errors can be detected in these cells and revealing a mechanism that regulates anaphase progression. This mechanism does not appear to rely on several components of the spindle assembly checkpoint but does require the kinetochore, as depleting kinetochore components prevents the error-induced anaphase delays. These findings therefore suggest that in this system, kinetochores could be involved in sensing meiotic errors using an unconventional mechanism that does not use canonical end-on attachments.
Authors: Amanda C. Davis-Roca, Christina C. Muscat, Sarah M. Wignall
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Amanda C. Davis-Roca, a graduate student in Wignall's lab, was the first author on the study published in March, "Caenorhabditis elegans oocytes detect meiotic errors in the absence of canonical end-on kinetochore attachments." Timothy J. Mullen, another graduate student in Wignall's lab, was first author on the study published in September, "Interplay between microtubule bundling and sorting factors ensures acentriolar spindle stability during C. elegans oocyte meiosis."
Abstract: Interplay between microtubule bundling and sorting factors ensures acentriolar spindle stability during C. elegans oocyte meiosis
In many species, oocyte meiosis is carried out in the absence of centrioles. As a result, microtubule organization, spindle assembly, and chromosome segregation proceed by unique mechanisms. Here, we report insights into the principles underlying this specialized form of cell division, through studies of C. elegans KLP-15 and KLP-16, two highly homologous members of the kinesin-14 family of minus-end-directed kinesins. These proteins localize to the acentriolar oocyte spindle and promote microtubule bundling during spindle assembly; following KLP-15/16 depletion, microtubule bundles form but then collapse into a disorganized array. Surprisingly, despite this defect we found that during anaphase, microtubules are able to reorganize into a bundled array that facilitates chromosome segregation. This phenotype therefore enabled us to identify factors promoting microtubule organization during anaphase, whose contributions are normally undetectable in wild-type worms; we found that SPD-1 (PRC1) bundles microtubules and KLP-18 (kinesin-12) likely sorts those bundles into a functional orientation capable of mediating chromosome segregation. Therefore, our studies have revealed an interplay between distinct mechanisms that together promote spindle formation and chromosome segregation in the absence of structural cues such as centrioles.
Authors: Timothy J. Mullen, Sarah M. Wignall
We thank members of the Wignall lab for support and thoughtful discussions, Amanda Davis-Roca, Nikita Divekar, Carissa Heath, and Ian Wolff for critical reading of the manuscript, and Bruce Bowerman, Marie Delattre, Arshad Desai, and Michael Glotzer for reagents. We also thank Jessica Hornick of the Northwestern University Biological Imaging Facility, members of the Andersen Lab, and Rachel Ng for technical assistance. Some strains were provided by the Caenorhabditis Genetics Center, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
Funding for this research was provided by the Damon Runyon Cancer Research Foundation and the March of Dimes Birth Defects Foundation (grant number is #5-FY13-197).
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(TOP LEFT) Spindle is football-shaped and physically separating chromosomes by pulling them apart during cell division. BLUE colors the chromosomes, GREEN fibers called microtubules which attach to the chromosomes. RED protein marks each of the two spindle ends.
(BOTTOM RIGHT) Spindle where two proteins - KLP-15 and KLP-16 - were chemically "knocked out," causing spindle structure to collapse into a disorganized round ball.
Image Credit: Sadie Wignall, Northwestern University