By Sean Henahan, Access Excellence

The new findings will help unravel one of the persistent questions in embryology, namely, how does a perfectly symmetrical oocyte go about differentiating and forming an asymmetric organism with head, tail, front back and so on? The Harvard researchers now report that the necessary RNA molecules for forming the organism are directed through the endoplasmic reticulum, in association with an endoplasmic reticulum-associated protein called Vera (VgLE binding and endoplasmic reticulum association).

Embryologists have long observed the asymmetric localization of RNA in oocytes. Even before fertilization, the oocyte sorts its RNA and strategically places RNAs that encode particular genes. The oocyte is primed to begin differentiating as soon as it it fertilized and becomes a zygote.

In studies with frog (Xenopus laevis) oocytes, Bruce Schnapp and colleagues found that an RNA encoding a growth factor called Vg1 migrates 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.

To prove that this protein was indeed necessary for RNA localization, the scientists 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 is the first experiment to make the connection between a protein and the mechanism of RNA localization. The researchers were surprised to find that the protein was loosely associated with the endoplasmic reticulum, the organelle better known for its role in protein synthesis. This specialized type of endoplasmic reticulum forms when the Vg1 RNA begins it migration to the cell's bottom.

Schnapp speculates that 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. His colleagues are following up on hints that there may be many more proteins, even a new cellular particle, involved in this process.

These findings also underscore the importance of basic biological research, Schnapp notes, adding that is becoming incresingly difficult to secure federal funding for this kind of work. 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.

The work appears in the May 16, 1997 issue of Science.