Cell Biology, Developmental Biology
University of Michigan
Dr. Yamashita is also a research associate professor in the Life Sciences Institute and an associate professor in the Department of Cell and Developmental Biology at the University of Michigan Medical School.
Deciphering Asymmetries in Stem Cell Division
Among the first words that Yukiko Yamashita spoke as a toddler were "Albert Einstein" and "Nobel Prize"—thanks to her physicist-trained father. "For as long as I can remember," she says, "I felt something almost sacred about science, and that the pursuit of truth was the best thing you can do in your life."
But being a scientist wasn't easy for a Japanese woman at Kyoto University in the 1990s. There were few women mentors or role models, and the Japanese culture frowned on women working outside the home. So after Yamashita earned her PhD degree studying yeast genetics, she and her husband looked for a new start elsewhere. Interviewing separately for positions, they became postdoctoral fellows in neighboring labs at Stanford University.
That's when Yamashita became fascinated with stem cells—and by one central question in particular: when a stem cell divides, what determines which daughter cell will remain a stem cell and which will differentiate into sperm, egg, or another tissue type? It's a crucial question because organisms must maintain a delicate balance between the numbers of stem cells and of differentiated cells. "If there are too many stem cells, you can end up with cancer," Yamashita explains. "But if there are too few, you can get tissue degeneration."
Yamashita began her work in Margaret Fuller's lab at Stanford with what everyone thought would be a small project, confirming that stem cell division in the fruit fly testes mimicked what had already been seen in female germline stem cells. But when she found that in the male germline stem cells the orientation of the mitotic spindle, the structure that separates chromosomes, is prepared much earlier than expected, the project became bigger than she anticipated.
Probing further at Stanford and then in her own lab at the University of Michigan, Yamashita made numerous discoveries that are transforming the study of stem cells. She showed, for instance, that stem cell division is asymmetric in many unanticipated ways. When the stem cell divides, the daughter cell that retains the original "mother" copy of a cell structure called the centrosome is the one that remains a stem cell. Her lab also uncovered a key checkpoint in this asymmetric cell division—showing that the position of the centrosome determines whether or not cell division will continue.
Yamashita's finding that the mother centrosome stays with the stem cell daughter (rather than going to the daughter destined for differentiation) was seen by some scientists as support for the idea of "immortal strands"—mother chromosomes that also remain with the stem cell. But when Yamashita and her students developed a method for precisely charting the fate of chromosomes, they conclusively refuted the immortal stand idea. Instead, she found, the original chromosomes and the copies are nearly evenly split between the two daughter cells. There is one surprising exception, though. The lab group recently discovered that the original X or Y chromosomes end up in the stem cell daughter 85 percent of the time. No one had expected that those chromosomes would be different from all the others, and it was also striking that the mother-daughter ratio was so consistent.
"I was totally shocked," says Yamashita. "That 85-15 split is something we are now trying to understand." She is exploring whether it is the result of epigenetic changes (alterations in the material associated with genes) carried down from previous generations.
Yamashita is also investigating what makes the mother centrosome special. She and a postdoctoral fellow have found a protein that, when mutated, causes that centrosome—but not the daughter centrosome—to grow up to 10 times longer. By figuring out the interactions of the protein, she hopes to chart the regulatory pathway of the mother centrosome.
Yamashita's research has received many accolades, including a MacArthur Fellow award in 2011, giving her extra confidence to take risks. "When I try to do something new, I always fear it might be too crazy," she says. "Now I think, maybe there is some value in what I am doing, so I have the courage to keep going."