In early embryos, cilia get the message across

LA JOLLA, CA - Having your heart in the right place usually means having it located on the left side of your body. But just how a perfectly symmetrical embryo settles on what's right and what's left has fascinated developmental biologists for a long time. The turning point came when the rotational beating of cilia, hair-like structures found on most cells, was identified as essential to the process.

Now, scientists at the Salk Institute for Biological Studies take a step back and illuminate the molecular process that regulates formation of cilia in early fish embryos. In a study published in a forthcoming issue of Nature Genetics, the Salk team, led by Juan Carlos Izpisúa Belmonte, Ph.D., a professor in the Gene Expression Laboratory, identified a novel factor that links early developmental signals with the function of cilia and their role in controlling left-right specification in zebrafish.

"When we altered the function of the gene duboraya, we saw problems with cilia formation, although the gene product itself is not a part of the structure. This opens up a new area of research," says Belmonte.

Cilia have been known to cell biologists for over a hundred years. Belmonte is convinced that these humble structures, which have until recently been ignored by physiologists and molecular biologists alike, are poised to take center stage in the field of biology. Explains Belmonte: "When you impair the function of cilia or the flow of cilia, you create substantial problems throughout the body."

These simple, whip-like structures are not only critically involved in specifying left-right sidedness during development, but they help move fluid and mucus around the brain, lung, eye and kidney, and are required for smell, sight and reproduction. Medical conditions, such as diabetes and obesity, have been linked to structural defects in the architecture or in function of cilia. Moreover, recent evidence indicates that cilia may have additional roles in controlling skeletal development and brain function.

Cilia on the outer surface of the embryo's underside, an area called the ventral node in mammals, exhibit a characteristic twirling movement that wafts chemical messengers over to the left side. This sets up a chemical concentration gradient that tells stem cells how and where to develop. When cilia function is impaired, organs like the heart, lungs, and liver may end up on the wrong side of the body.

When postdoctoral researcher and first author Isao Oishi, Ph.D., searched for genes in zebrafish involved in the left-right patterning of early embryos, he expected to find genes encoding components of cilia. "Instead we found a non-structural cilia gene that influences the function of the cilia, and that, among other things, caused problems with left/right patterning," he says. He named the gene duboraya after the shape of the Japanese duboraya lantern, which fish with an inactivated version of the gene assume as they develop.

Oishi discovered that duboraya is required for formation of fully functional cilia in Kupffer's vesicle, the fish equivalent of the mammalian ventral node. Without duboraya, cilia were reduced to short stumps, unable to create the counterclockwise flow needed to establish left versus right. Duboraya protein, he found, is activated by frizzled-2, a member of the highly conserved Wnt signaling pathway, which orchestrates the activities of a vast number of cells during embryonic development.

Explains Belmonte: "We could show that genes that sense their external or internal environment communicate with structural genes that are responsible for making the cilia and tell them to beat this way or that way. What Isao discovered is a mechanism of how they relay information."

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Researchers who contributed to the work include postdoctoral researchers Yasuhiko Kawakami, Ph.D., and Carles Callol-Massot, Ph.D., both at Salk, and Ángel Raya, M.D., Ph.D., formerly at Salk and now scientific co-ordinator at the Center of Regenerative Medicine in Barcelona, Spain.

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.


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