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Electric Field May Control Early Embryo Asymmetry

Researchers at the Forsyth Institute and HMS have discovered that asymmetric gradients of potassium and hydrogen ions in the embryo determine left-right asymmetry in vertebrates. They also have located the genetic material that encodes for this mechanism and have determined that the process through which a fertilized egg begins left-right patterning begins in a matter of hours.

Appearing in the Oct. 4 Cell, the findings have important ramifications for understanding human conditions such as left-right hand preference, mirror image twins, right- vs. left-brain dominance, and birth defects that cause organs to develop on the wrong side of the body, according to first author Michael Levin, HSDM assistant professor of oral and developmental biology and an assistant member of the staff at Forsyth.

"We are only beginning to address the mysterious evolutionary and developmental origin of asymmetry--the first step which allows the embryo to reliably know its left from its right," Levin said. "Orienting the left-right axis is crucial for later stages of development since it controls not only the shaping of the asymmetric visceral organs but also of the brain."

The study also sheds light on the shaping of tissues and may have implications for organ regrowth and the treatment of cancer, which can be seen as a disorder in which cells lose the ability to assume their proper position.

Working with frog and chick eggs, the researchers determined that a molecular ion pump, dubbed H+/K+-ATPase, sets up gradients of K+ and H+ ions that are asymmetric across the midline of the embryo, and that these gradients are required for correct left-right asymmetry. The researchers also found an asymmetric localization of mRNA for this pump at the four-cell stage, which shows for the first time that asymmetry is assigned far earlier than was previously believed--within two hours of fertilization.

"We now have a new handle on molecular mechanisms by which natural electric fields are set up and serve to control cell behavior and tissue shape," Levin said. "We believe that this knowledge will increase our ability to control cell function in biomedical contexts such as tumor growth control and limb regeneration."

Asymmetric function of the ion pump regulates cascades of gene expression that in turn provide cues to the developing organs, instructing their asymmetric development.

"This is extraordinarily important because it provides the earliest known mechanism for determining left-right asymmetry," said senior author Mark Mercola, professor in the stem cell and regeneration program at the Burnham Institute in La Jolla, Calif. It was in Mercola's previous lab at HMS that much of the work was carried out while Levin was a fellow there. "The mechanism of an electrical current being involved in early patterning is an extremely novel idea that opens up new avenues of research."

"For years, scientists have been thinking about the importance of the many electric fields which are set up by cells and tissues," explained Mercola. "This finding shows a specific function for the establishment of a body's axis--a function that has never been considered before."

Clifford Tabin, HMS professor of genetics, called the study "a major breakthrough, tracing the origin of left-right organization to the very first stages of embryonic development and implicating a regulatory mechanism heretofore unrecognized for its significance in this context: the control of ions moving across cell membranes by the so-called H+/K+-ATPase."

Every year in the U.S., approximately one in 8,000 babies is born with laterality defects in which internal organs are misplaced, leading to serious deficits in function. The current research sheds light on a new cause of these conditions.

--Adapted from Anita Harris