Using the technique, the investigators found and followed the cells that turned on the p48 gene--as if these cells were wearing blue hats. The cells that bud out to form the pancreas turned on p48; they were blue. And the cells of the mature pancreas were blue too.
Wright's team combined this powerful method for tracing a cell's lineage with gene knockout technology. They engineered mice to lack the p48 gene, causing abnormal development of the pancreas. Cells in these knockout mice still try to turn on the p48 gene, so the investigators were able to follow the blue marker in these cells.
They found that, with p48 absent, the cells that normally express p48 and go on to form pancreas became intestinal cells instead. And they became all types of cells in the intestines, including intestinal stem cells. It is the first time, to Wright's knowledge, that investigators have tracked what happens to cells when a gene that they normally turn on is missing.
"The really important point is that these cells don't just die; they go on to behave as a different tissue," he said. "That is very powerful information when you are thinking about manipulating stem cells in the laboratory. Because you know now--at least for some genes--that you can put them in or take them away and you don't kill the cells; you manipulate what they're going to become. And that's exactly what we want to do therapeutically."
Wright believes that linking lineage tracing and gene knockouts will become increasingly common. "It adds extra depth to understanding cellular behavior," he sai
Contact: John Howser
Vanderbilt University Medical Center