Mar. 15, 2001 Like a restless Romeo forever seeking the perfect embrace, a developing nerve cell reaches its final destination in the brain by drawing close to one target, then turning to a series of newer attractions as it continues on a halting course toward a predestined rendezvous with another nerve cell.
Scientists at the University of California, San Francisco have discovered how an advancing axon is able to turn away from an attractive target almost as soon it is reached. The strategy allows the pioneering nerve to continue on its journey even though the attractive site continues sending signals to stay. The behavior prevents pioneering nerves from backtracking and laying down faulty wiring that could spell disability or death to the embryo.
The discovery of how axons can simply "walk away" from an attractant is reported in the March 9 issue of the journal Science. The finding involves an unsuspected physical engagement -- a duel with a predetermined outcome -- between two different kinds of receptors on the axon. One receptor is normally dedicated to receive attractive cues, while the other is tuned to repellent cues that guide the axon's direction of movement. But when an axon encounters attractant and repellent cues together, the receptors take on a new role, the scientists found. Instead of acting separately, they interact - and always with the same outcome: the repellent receptor blocks the attractant receptor. As a result, the axon can continue on an unambiguous course.
"It is as if we are reading the instructions in the rule-book used to wire up the brain," says Marc Tessier-Lavigne, PhD, Howard Hughes Medical Investigator and professor of anatomy and of biochemistry/biophysics at UCSF, and senior author on the Science paper.
"The rule here is that when the axon is capable of sensing both attraction and repulsion and both types of signals are present, then repulsion dominates - attraction is switched off. The rule is clearly designed to prevent the axon from becoming confused, which could have disastrous consequences to the developing embryo."
In just the last eight years, studies in fruit flies, mice and humans have allowed scientists to identify "guidance molecules" expressed in the embryonic nervous system as well as receptors on the advancing axon that are tuned to these molecules. The interaction between the two either attracts or repels the migrating axons on their initial journey in the embryo. Researchers at UCSF and UC Berkeley did much of the initial work, identifying an attractant dubbed netrin and repellents named semaphorin and slit, as well as their receptors.
In 1998, scientists discovered that when an embryonic nerve is drawn by an attractant to a target and then encounters both attractant and repellent signals, it responds only to the repellent, ignoring the attractant. As a result, it won't tarry at the once-attractive site but moves on. The new report in Science clarifies how the axon sifts the information in this "mixed signal," first extracting the attractive information, then dramatically switching its behavior to ignore attraction and only perceive the repulsive information. The new research also establishes that the mechanism actually predetermines the outcome any time an axon encounters conflicting guidance signals.
Perhaps the simplest way an axon could be coaxed to move away from an otherwise-attractive target might be to swamp the attractive signals with repellent cues.
But the UCSF scientists discovered that the axon's behavior is not dictated by the sum of all positive and negative signaling molecules. Rather, they found, the axon's receptors for the repellent molecule - a receptor dubbed Robo - physically block the performance of receptors for the attractive signal, in effect, silencing them. Their research shows that the outcome of the interaction is predetermined, the scientists say.
Tessier-Lavigne and post-doctoral scientist Elke Stein identified specific "modules" in the repulsive and attractive receptors that are dedicated to triggering the silencing effect.
Using a previously described isolated frog spinal axon as an assay, they showed that in the presence of both the attractant and repellent signals, an element on the axon's repellent receptor, Robo, physically binds to an element on the attractant receptor called DDC, inactivating it. In this condition, the axon is no longer in the throes of attraction and is ready to move on.
In what a commentator in the Science issue called a tour de force, Tessier-Lavigne and Stein reduced the complex system of signals and receptors to their elemental parts and showed how specific modules in each receptor protein interact to trigger the silencing effect of repulsion on attraction. They first replaced the netrin- and slit -signaling molecules with others to show that it was not the signals that mediated the silencing effect. They then removed the interacting sites on each receptor and showed that the silencing effect was lost. Finally, they replaced these interacting sites with synthetic sites and showed that the silencing effect was restored - because the receptors were once again able to bind. The series of experiments demonstrate that it is a physical interaction between the receptors that turns attraction off.
The research was supported by the Howard Hughes Medical Institute.
NOTE: A diagram of the basic discovery can be accessed at: http://pubaffr.ucsf.edu/imagedb/imsearch.php3?iname=03022001
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