Researchers from the University of Chicago have uncovered an important mechanism used by the developing brain to pattern nerve connections in the part of the brain that interprets visual signals. In the process, they have provided the first experimental evidence for a decades-old model of how nerve cells establish distant connections in a way that can consistently relay spatial information.
In the January 5, 2006, issue of the journal Nature, the researchers show that a gradient of a molecule known as Wnt3 counterbalances another force provided by the EphrinB1-EphB signaling system. The balance between these two signaling systems, they show, is necessary to establish the carefully controlled pattern of nerve connections required to convey spatial information in the correct order from the eye to the brain.
"This is the first biological validation of a computational model developed in the early 1980s that suggested that two such forces would be necessary to guide axons as they establish the connections that relay spatial information from one part of the nervous system to another," said study author Yimin Zou, Ph.D., assistant professor of neurobiology at the University of Chicago.
Neurobiologists refer to this type of neuronal connection -- in which the spatial order of neurons of one part of the nervous system is "copied" onto another -- as "topographic mapping." The term describes the creation of a coordinated connection that allows positional information from a grid of sensors, in this case the light-sensitive cells in the retina, to be smoothly and systematically transferred to their target, the structures in the brain that interpret information from the eyes.
"Without an orderly and faithful connection," said Zou, "information from the eyes could not be properly deciphered by the brain."
"Topographic maps are a very common wiring strategy in our brains," he said. Similar systems are thought to regulate other sensory systems -- such as hearing and touch, as well as motor systems -- but the visual system has been the predominant model system for studying the development of such maps and the gradients of guidance molecules that control their formation.
Scientists have searched for these gradients, the global positioning system of the brain, for more than forty years.
In 1963, neurobiologist Roger Sperry (who won the Nobel Prize in 1981) proposed the "chemoaffinity hypothesis." Sperry suggested that chemical signals, probably present in concentration gradients, serve as positional landmarks within the brain. Theses landmarks are then recognized by growth cones at the tip of axons -- the projections that grow out from the retinal neurons and into the brain. The wandering axons use these signals to locate their destinations in the map.
Twenty years later, in 1983, Alfred Gierer developed computational models of this process. His models indicated that at least two counterbalancing signaling systems were required to push and pull the growing and branching axons as they searched for their ultimate topographic positions within the brain.
In the 1990s, scientists found the first of those signaling systems, a family of ephrin proteins that are present in graded fashion in the brain and are involved in axon guidance. The A-class ephrins are required for map formation along the anterior-posterior (front-to-back) axis and the B-class for medial-lateral (side-to-side) axis.
For several years, Zou's lab has been studying a different family of proteins, known at the Wnts. Although Wnts were better known because of their role as morphogens -- proteins that pattern bodily structures and determine cell fates -- Zou recently showed how members of the Wnt family served to guide pathfinding axons up and down the spinal cord by attracting or repelling receptors on the growth cones of sensory or motor nerves.
In this paper, Zou and colleagues reveal a new role for Wnts. They show that a gradient of Wnt3 along the medial-lateral axis within the developing brain is the opposing regulating force, working along with ephrinB1 to specify the topographic target selection in the optic tectum, a brain region that processes information from the eye.
At the molecular-signaling level, Wnt3 acts through two different classes of growth-cone receptors, Ryk and the Frizzled(s), to pattern topographic connections in the brain. Disrupting either the Wnt or ephrin pathway throws the growing axons off their targets, shifting the map from side to side.
This counterbalancing force has two components, Zou's team discovered, with one receptor drawn toward certain concentrations of Wnt3 and the other driven away. "A repulsive Wnt-Ryk pathway competes with an attractive Wnt-Frizzled interaction," the authors write, "to titrate the response to Wnt3 protein at different concentrations." The net outcome of the competition, they conclude, "determines the topographic connections by providing a lateral directed mapping force."
The research was supported by the National Institutes of Health, the Alfred Sloan Foundation, and the Schweppe Foundation. Additional authors of the study include Adam Schmitt, Jun Shi, Alex Wolf, Chin-Chun Lu and Leslie King at the University of Chicago.
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