Three-Way Switch Directs Mouse Embryo Cell

Researchers have pinpointed a genetic "master switch" that directs the developmental fate of embryonic stem cells from mice. If true for human cells too, the finding could help researchers grow specialized cells in the laboratory to replenish damaged or diseased tissue.

Two years ago, researchers for the first time found a way to keep human embryonic stem cells growing in culture. This was a coup because these cells normally develop into bone, muscle, liver, or any other tissue type. Many scientists think undifferentiated stem cells hold great medical promise, but they know very little about the molecular signals that tell stem cells to specialize. One thing is clear: In embryos just a few days old, cells begin to sort themselves into three tissues: the trophoblast, which becomes the placenta; the epiblast, which produces cells surrounding the embryo that help direct its development; and the inner cell mass, which develops into the embryo itself.

In previous experiments, Austin Smith and his colleagues at the University of Edinburgh, United Kingdom, had shown that embryonic mice without a gene called Oct-4 could not form an inner cell mass. To see if Oct-4 was directly responsible for determining the fate of embryonic stem cells, the team genetically altered the cells so that they could control the amount of Oct-4 protein produced in the cells.

Cells that made normal Oct-4 quantities kept growing as embryonic stem cells, the team reports in the April issue of Nature Genetics, but cells that made just twice as much Oct-4 developed behavior typical of epiblast cells, such as clinging to the surface of the culture dish rather than to other cells. Turning off Oct-4 altogether, on the other hand, caused the stem cells to become trophoblast cells. The results mean that Oct-4 is a three-way switch, the researchers conclude; cells go down one of three developmental pathways depending on their amount of Oct-4.

"It's a nice simple model of how early embryonic development might occur," says developmental biologist Janet Rossant of the University of Toronto. And knowing about the switch--as well as many others that must exist--may help researchers coax embryonic stem cells to become particular tissue types, she says.