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Harvard Medical School Researchers Discover Protein That Explains How Egg Cells Prepare To Become Embryos

Harvard Medical School

BOSTON--May 8--It's never too early to start getting organized.

The embryo is clearly heeding this lesson--so much so, indeed, that the unfertilized egg already prepares for the long developmental journey ahead by putting its house in order even before it meets a sperm. The oocyte sorts its RNA, the genetic material needed to translate the DNA blueprint into an organism, and places RNAs that encode particular genes into particular corners. That way, the oocyte ensures that if it is lucky and gets fertilized, the first cell divisions cleaving the zygote will yield daughter cells with different RNA contents, which will send them on different developmental paths.

This process, called RNA localization, sets the stage for the embryo's ability to blossom from a single cell into a body with broad cell and tissue diversity. Yet the mechanism has been mysterious. Until now, that is.

In the May 16 Science, HMS associate professor of cell biology Bruce Schnapp and his coworkers report the discovery of a novel protein that begins to bring an understanding of how the oocyte moves its RNAs to the right places. Moreover, the work for the first time implicates a component of the cell's infrastructure, the endoplasmic reticulum (ER), in this process, describing a new subtype of ER and suggesting a new role for this well-studied organelle.

This research could attain broad importance in biology because RNA localization occurs in many adult cell types, including brain and muscle cells. It also might be involved in asymmetric cell divisions throughout later stages of embryogenesis.

At the beginning of this century, scientists noticed pigmented dots in the eggs of certain animals. As they watched the fertilized egg divide, they saw the dots appear in some of the daughter cells but not others, suggesting that such "asymmetric" cell divisions could somehow create cell diversity. Like many descriptive notions in embryology, this idea went "molecular" in the 1980s, when researchers led by Nobel laureates Christiane Nüsslein-Volhard and Erich Wieschaus of Germany studied the genetics of fly development. They found, among other things, that all the steps of forming the basic body patterns in the early embryo--such as designating head and tail, back and belly, left and right--originated with the transport in the oocyte of specific RNAs to specific spots.

"This had a huge influence on me," recalls Schnapp. "It is what got this research started."

Schnapp and postdoctoral fellows James Deshler and Martin Highett focused on the RNA encoding a growth factor called Vg1. In maturing frog oocytes, Vg1 RNA travels to the "bottom," or vegetal pole, of the egg. After fertilization and several cell divisions, this RNA becomes restricted to cells in the vegetal area, and the Vg1 protein made from this RNA then signals the overlying cells to turn into mesoderm, one of the embryo's three germ layers. (A two-color diagram is available upon request.)

The researchers knew that the genetic "address label" for localization was hidden somewhere in a certain region of the RNA. Using this region as a probe, they identified an unknown protein that bound to it. To prove that this protein was indeed necessary for RNA localization, they pinpointed the exact spots in the RNA that recognized the protein, created mutants that were defective in these spots, and then demonstrated that when the RNA no longer bound the protein, it also no longer headed for the bottom of the egg.

This experiment for the first time directly ties a protein to the mechanism of RNA localization, says Schnapp. But it was only the beginning of the study. Next, the researchers found that their protein was loosely associated with the ER. That was surprising, because researchers had never suspected the ER of trafficking RNA. The traditional view holds that this expansive membrane system, which meanders throughout the cell, deals in proteins: It receives proteins through channels and sorts them for delivery to their ultimate destination.

Schnapp's team, however, discovered that in maturing oocytes, a specialized sort of ER takes shape right at the time when the Vg1 RNA sets out for the cell's bottom. What's more, this ER and Vg1 RNA appear to be moving in tandem. This has Schnapp excited because it begins to dovetail with his previous research into a different field, molecular motors. These proteins transport cargo--such as snippets of ER--along rodlike parts of the cell's inner skeleton, called microtubules. Intriguingly, microtubules are known to establish a system of direction, much like a compass, within the oocyte, says Schnapp.

Maybe, he speculates, the new protein--dubbed vera for Vg1 ER associated protein--somehow hooks up Vg1 RNA with this specialized ER, which then travels along microtubules to the vegetal pole, taking the RNA along for the ride--

The exact function of vera is still unknown, he cautions. Like much early work that opens new research avenues, this study raises more questions than it answers. But at least scientists now have a handle on how to study the problem. "Before, there was no way in which one could think about the mechanism. It was completely murky," says Schnapp. He hopes vera will lead him to novel machinery the cell uses to transport RNA. Already, Deshler, Highett, and postdoc Eric Arn are following up on hints that there may be many more proteins, even a new cellular particle, involved in this process.

Unraveling this machinery is particularly gratifying, says Schnapp, because the project was exploratory, the sort of work for which it has become nearly impossible to secure NIH funding. As was the case with many fundamental discoveries in cell biology, there was no prior data suggesting a specific hypothesis that should be tested--the standard approach taken in most grant proposals. "This work finally self-assembled out of five years of exploration. It came out of thin air," Schnapp says.

-end-

Editors: Schnapp is available for interviews upon request, as is a two-color diagram that illustrates the story. The URL for Schnapp's web page is http://cbweb.med.harvard.edu/research/schnapp/

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