How Chromosomes Align Perfectly When Dividing
by Nicole Giese Rura
To solve a mystery, a great detective need only study the clues in front of him. Tomomi Kiyomitsu used his keen powers of observation to solve a puzzle that had mystified researchers for years: in a cell undergoing mitotic cell division, what internal signals cause its chromosomes to align on a center axis?
"People have been looking at these proteins and players in mitosis for decades, and no one ever saw what Tomomi observed," says Whitehead Institute Member Iain Cheeseman. "And it's very clear that these things are happening. These are very strong regulatory paradigms that are setting down these cell division axes. And careful cell biology allowed him to see that this was occurring. People have been looking at this for a long time, but never with the careful eyes he brought to it."
Kiyomitsu, a postdoctoral researcher in Cheeseman's lab, published his work in this week's issue of the journal Nature Cell Biology.
The process of mitotic cell division has been studied intensely for more than 50 years. Using fluorescence microscopy, scientists can see the tug-of-war cells undergo as they move through mitosis. Thread-like proteins, called microtubules, extend from one of two spindle poles on either side of the cell, attempting to latch onto the duplicated chromosomes. This entire "spindle" structure acts to physically redistribute the chromosomes, but it is not free floating in the cell.
Microtubules attach to both spindle poles and all the chromosomes. Astral microtubulesare also connect to the cell cortexa protein layer lining the cell membranepulling the spindle poles back and forth within the cell until a perfect alignment exists down the center axis of the cell. Microtubules then tear the duplicated chromosomes in half, so that only one copy of each chromosome ends up in each of the new daughter cells.
The process of mitosis is extremely precise when it comes to manipulating DNA. Gaining or losing a chromosome during cell division can lead to cell death, developmental disorders, or cancer.
As Kiyomitsu watched mitosis unfold in dividing human cells, he noticed that when the spindle oscillates toward the cell's center, a partial halo of the protein dynein lines the cell cortex on the side farthest from the spindle. As the spindle swings to one side, dynein appears on the other, reversing their positions with each oscillation.
For Kiyomitsu, the key to the alignment mystery is dynein. Dynein is known as a motor protein that "walks" molecular cargoes along microtubules.
Kiyomitsu determined that during mitosis, dynein is anchored to the cell cortex by a complex including LGN, short for leucine-glycine-asparagine-enriched protein. Instead of moving along an astral microtubule, the stationary dynein acts as a winch pulling the spindle pole toward the cell cortex, along with the microtubules and chromosomes attached.
Kiyomitsu observed that when a spindle pole comes close to the cell cortex, a protein called Polo-like kinase 1 (Plk1) emanates from the spindle pole and knocks dynein off of LGN. This action stops the spindle pole's forward motion, freeing dynein to move to the opposite side of the cell. These oscillations continue until the spindle settles along the cell's center axis.
Kiyomitsu also noticed that LGN is layered all around the cell cortex, but not immediate to the chromosomes. Because dynein needs to anchor to LGN, this clear area ensures dynein will only attach and pull to the right and left of the aligning chromosomes, and not from above or below.
Kiyomitsu: "The spindle orientation is critical for maintaining the balance between stem cells and mature cells during development. And if this orientation becomes dysregulated or misregulated, it is reported that this may contribute to causing cancer even if chromosomes are properly segregated."
This work was supported by the Massachusetts Life Sciences Center, the Searle Scholars Program, and the Human Frontiers Science Foundation, the National Institutes of Health (NIH)/National Institute of General Medical Sciences, and the American Cancer Society.
Iain Cheeseman's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also an assistant professor of biology at Massachusetts Institute of Technology.
"Chromosome and spindle pole-derived signals generate an intrinsic code for spindle position and orientation"
Nature Cell Biology, published online February 12, 2012
Tomomi Kiyomitsu (1) and Iain M. Cheeseman (1)
1. Whitehead Institute, Nine Cambridge Center Cambridge, MA 02142
Original article: http://www.eurekalert.org/pub_releases/2012-02/wifb-amm020812.php