All turned around. In an embryo treated with a drug that blocks the 14-3-3 protein (right), the heart (red arrow), the gut (yellow), and gall bladder (green) are on the wrong side.

How Embryos Know Left From Right

Every organ has its place in the human body. The gallbladder goes on the right side, the spleen on the left, for example. Now scientists have found an embryonic protein in frogs that sets up the difference between left and right. The protein causes this differentiation to happen earlier in the developing embryo than previously thought.

About one in every 8000 babies is born a bit mixed up. Some combination of the heart, stomach, and other innards wind up on the wrong side of the body, causing medical problems. Scientists don't understand how this happens, although some researchers are tracking down genetic mutations.

The new insight was fortuitous. Developmental biophysicist Michael Levin of the Forsyth Institute in Boston, Massachusetts, and colleagues noticed that a drug they were studying for a different reason skewed the left-right axis in frog embryos. Curious, they bathed newly fertilized eggs in the drug for part of their development, then washed the drug out long before the embryos grew organs. The team found that 25% of the drug-treated frogs had misplaced hearts, stomachs, and/or gall bladders, compared to 1% of the untreated animals. The researchers tracked down the frog protein that the drug acted upon and found a poorly understood protein called 14-3-3.

The team found that after the fertilized eggs divided for the first time, the 14-3-3 protein resided in only one of the two cells, revealing that 14-3-3 directs the left-right axis at a surprisingly early stage of development. "That nails down when the axis is set up to about an hour after fertilization," Levin says. When the researchers overproduced 14-3-3 protein in embryos, the protein settled into both cells. One explanation for the misplaced protein is that another frog molecule directs 14-3-3 to the correct cell, says Levin, and when there's more 14-3-3 present than the mystery molecule, the protein overwhelms the molecule and spills into the other cell, resulting in frogs with organs in the wrong place. The team reports its findings in the 20 October issue of Development.

The paper is "definitely significant" because it gives "new insight into the early pathways of patterning," says developmental biologist Rebecca Burdine of Princeton University. Although the 14-3-3 proteins aren't well understood, she says, related proteins play a role in organizing development in invertebrates, which suggests that 14-3-3 pathways could be very widespread in nature. "That's very cool," she says.

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Levin's lab at the Forsyth Institute