January 19, 2017
Fluorescence microscopy image showing neural stem cells (green) in a mouse brain. Zhao is trying to better understand how these neural stem cells develop into specialized nerve cells at certain locations in the adult brain. (Image provided by Xinyu Zhao)
Stem cells are remarkable cells that have the ability to become almost any kind of specialized cells in our bodies. Given this extraordinary potential, how does a stem cell keep from having an identity crisis?
SCIENCE ON THE SIDE
All the cells in our bodies, including stem cells, have essentially the same DNA. Yet, we have muscle cells, liver cells, skin cells, all kinds of specialized cells. How do these different kinds of cells develop if the genetic information in each of them is the same?
The answer lies partly with chemical tags that modify our DNA or the proteins around which our DNA is packaged. These tags (shown as glowing orbs in the illustration above) act like Post-it notes, providing information that helps stem cells develop into different kinds of specialized cells, such as a nerve cell.
The study of these tags – information in addition to what’s contained in our DNA – is called epigenetics.
A recent study from Waisman Center researcher Xinyu Zhao’s lab shows how a gene called MBD1 plays an important role in maintaining the identity of neural stem cells and regulating the stem-cell-to-nerve-cell pipeline in the brain.
Mice without MBD1 display several behavioral issues, including reduced social interactions, increased anxiety, and learning and memory deficits.
“Given all these behavioral issues, we wanted to study what happens to the formation of new neurons in the brains of mice that do not have the MBD1 gene,” says Zhao, who is a professor of neuroscience at UW-Madison.
Turns out, there are only a couple of places in the entire adult brain where new nerve cells are produced. One of these locations is a tiny banana-shaped area called the dentate gyrus, where there is a pool of neural stem cells. The dentate gyrus is thought to be important for learning, memory and the ability to adapt to a continuously changing world.
Emily Jobe, a graduate student in Zhao’s lab, analyzed mice that lacked the MBD1 gene. Zhao, Jobe and their colleagues found that in the dentate gyrus of these mice, neural stem cells seemed to stall in an unspecialized state – they were unable to become nerve cells efficiently.
To understand why the stem cells were stalling, Jobe used high-throughput methods to determine the levels of various gene products in the neural stem cells of mice with and without MBD1.
“She found that neural stem cells from the MBD1-deficient mice contained a number of gene products that are typically not present in stem cells,” says Zhao. “It's as if the stem cells are confused; they no longer know what they are supposed to be.”
In fact, when the researchers used a microscope to take a closer look at these neural stem cells, “they seemed to resemble neither stem cells nor nerve cells, but rather something in between,” says Zhao.
According to Zhao, it is critical that stem cells maintain their identity if they are to retain their ability to develop into specialized cells. “This is the first time someone has shown that MBD1 plays a pivotal role in maintaining the ‘stemness’ of neural stem cells,” she says.
The MBD1 protein “reads” specific tags – called methylation – that modify the DNA strands in our cells. These modifications are like chemical Post-it notes, and by reading and interpreting these DNA methylation “notes”, MBD1 regulates which genes are turned on or off in specific cells.
Zhao thinks that without MBD1 to interpret the DNA methylation, genes that should be turned off in neural stem cells get turned on instead, which results in the cells losing their stem-cell identity.
Learning more about how new neurons are generated in the brain could help us understand how our brains integrate new information in the short and long term.
“Every day we might have to remember where we parked our car, where we placed our keys, and so on,” says Zhao, “and we think that the new neurons being made at the dentate gyrus are key for the flexibility we need to survive, adapt and thrive.”
Zhao says there’s still a lot to learn about exactly how MBD1 helps neural stem cells maintain their identity and the roles new neurons play in learning and memory. “But a discovery like the one we have made is an important piece of a very large puzzle.”