How does a fruit fly egg label its rear end, and why should we care?

Did you ever wonder how a scientist has any fun, cooped up in the lab all day? It is easy to see the fun in field biology, where you get to study lizards on Caribbean islands, or track lions or live with mountain gorillas. But the biologist that grinds up cells and analyzes their innards — where is the fun in that?

Anyone that does laboratory science knows the answer. A scientist is a detective, a solver of puzzles, and laboratory science abounds in challenging puzzles that are a lot of fun to solve. I thought this week I’d introduce you to one.

The work I am going to describe is being carried out here in St. Louis, in the Washington University laboratory of Dr. Kathryn Miller. It concerns development in the fruit fly Drosophila. You might have encountered Drosophila as the tiny flies that sometimes dive into open glasses of wine. In the laboratory Drosophila is a so-called “model system,” one that biologists study in great detail in order to develop generalizations that can be applied to many organisms. Much of what we know of how genes direct human development, for example, was first learned in Drosophila.

Development in Drosophila has been the focus of intense research, and biologists have built up a detailed picture of how it proceeds. Many of the key events, it turns out, take place long before a sperm fertilizes an egg. And it is there that we go to encounter the puzzle that Kathy Miller is attempting to solve.

A Drosophila egg is organized far more complexly than a human one. The interior composition of a human egg is relatively uniform. After fertilization, a human egg divides rapidly several times, forming a ball of cells, each with similar contents. Any one of those cells contains everything needed to form an adult (indeed, it is from such cells that animals like Dolly the sheep are cloned).

Not so a Drosophila egg. Different segments of the egg’s interior have very different chemical contents, like a warehouse with different sorts of supplies stored here and there. As the egg divides into a clump of daughter cells, each daughter cell gets a different array of these supplies. Some get messenger RNA molecules that say “This is going to be the back end of the body,” other cells get messenger RNA molecules that destine them to become segments of the body, and still other get other signals.

Now lets focus for a moment on that “back end of the body” signal. Setting up the orientation of the future embryo with this signal is the first key step of Drosophila development. Laying down a front-to-rear axis orients the many complex events to follow, and sets some cells aside to become germline (sex) cells.

The “back end of the body” signal was identified five years ago to be a family of messenger RNA molecules with fanciful names like oskar. These messenger RNA molecules are in essence zerox copies of special location-determining genes that guide the course of Drosophila development. Oskar and its companion signals are produced from genes located in the nucleus of the egg, and then transported out of the nucleus and across the cell interior to the rear of the egg. How is this transportation achieved? Like taking a train to Chicago. The signal molecules are transported along rails called microtubules that extend through the interior of the egg cell like traintracks. Cell biologists call this transportation system the microtubule cytoskeleton — MT cytoskeleton for short.

Some of the signals, packaged in tiny membrane sacs, are attached to a “motor protein” Kathy has identified called CLIP. Other signals are attached to another motor protein called kinesin. CHIP and kinesin chug along microtubules like trains on tracks, dragging the signal packages to the rear of the egg.

Now for Kathy Miller’s puzzle. Once the signal packages arrive at their proper location, what keeps them there? What prevents the signals from simply drifting back towards the center of the cell?

There is a network of protein filaments just beneath the cell surface that might serve as an anchor. It is made of the protein actin, the same protein that makes muscles contract. A motor protein called 95F myosin moves along the actin filaments of this actin cytoskeleton. It is strictly for the local traffic, not the long-distance transport of the MT cytoskeleton. The principle function of the actin cytoskeleton is to anchor molecules to particular spots on the cell membrane

Miller looked to see if the Drosophila egg passes the package of signals from one cytoskeleton to the other when the signal package reaches the rear of the egg — like your transferring from a train to a taxi when you get to Chicago.

Looking carefully with a variety of sophisticated molecular tools, Miller and her co-investigator Valerie Vance have found that in the rear of the egg, the 95F myosin motor protein is closely associated with the CLIP actin motor protein! Finding two motor proteins from different cytoskeletons linked together, right where the transfer would have to take place, is a bit like finding Capulet and Montague (Romeo and Juliet) holding hands — so unexpected as to be almost surely significant.

This is an exciting result to biologists. The two “skeletons” of a cell play key roles in almost everything a cell does. Now we have a glimpse of how they co-ordinate their activities.

But “almost surely significant” isn’t enough. A clear demonstration of the transfer between cytoskeletons is called for. So the work goes on in Kathy Miller’s lab. Much more pointed questions can be asked, now Miller knows to focus on the interaction of CLIP and 95F myosin. Fun questions.

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