Co-authors (L to R) Yifeng Zhang, Markus Meister, Joshua R. Sanes, In-Jung Kim, and Masahito Yamagata,
A mouse is small, close to the ground. Hawks and cats may attack it from above, but not much comes at it from below. Yet Harvard University researchers have discovered that mice have a remarkable type of nerve cell in the eye, seemingly specialized to tell the animal when objects in its world move upward. The result raises new questions about the secret life of mice, but the purpose of the research was much more sober: devising new ways to identify nerve cells with specific functions in the normal and diseased brain. And along the way, the research uncovered a remarkable correspondence between the shape of the nerve cells and what they do. The work, led by neuroscientists Joshua R. Sanes and Markus Meister, is described this week in the journal Nature.
The scientists used advanced genetic methods to mark a single set of nerve cells in the mouse eye with a fluorescent label that reveals their structure and makes it possible to record electrical signals from them. A big surprise was that the cells’ structure gave away the secret of their function. Nerve cells in the eye typically have many thin fibers, called dendrites, that protrude in many directions from the center of the cell. “The structure of these cells, in contrast, resembles the photos you see in the aftermath of a hurricane, where all the trees have fallen down in the same direction,” says Meister, the Jeff C. Tarr Professor of Molecular and Cellular Biology at Harvard, and a member of the Center for Brain Science in the Faculty of Arts and Sciences. “There’s no other cell type in the retina that has that degree of directionality.” And remarkably, when electrical signals were recorded from the cell, it turned out to respond to objects moving in the direction that the dendrites pointed. “The lopsided arrangement literally directs the cell’s function,” adds Sanes, professor of molecular and cellular biology and Paul J. Finnegan Family Director of Harvard’s Center for Brain Science. “It is unusual to know what a cell does just by looking at it – but that is exactly what you can do in this case.”
The research builds on efforts by the Meister and Sanes lab over the past few years. Meister has been wondering how the eye communicates the visual scene to the brain through the electrical impulses in the optic nerve. Last month, in work published in the journal Science, he and a colleague, Tim Gollisch, described a new form of image encoding that could help explain how our visual perception happens so extraordinarily fast. At the same time, down the hall, Sanes was finding molecules that help nerve cells make the highly intricate connections that form the brain’s circuits. His most recent work was reported in the journal Nature in January. In that paper, he and postdoctoral fellow Masahito Yamagata showed that a set of molecules with the unlikely names “Sidekick” and “Dscam” help to generate proper connections in the eye. In continuing this work, they found another, related molecule, called JAM-B, that “lit up” the odd set of pointy cells. At that point, the two groups pooled their talents to find out what the cells did.
According to Sanes, “getting the electrical and molecular experts together is an exciting step in learning how the brain goes about its business.” Once the work was underway, the results came quickly: a new way to pick out a small fraction of cells united by a single structure and function. “The real importance is in proving a method that can now be applied throughout the brain,” says Meister. “There is a growing suspicion that many behavioral disorders occur because particular types of neurons connect incorrectly or do the wrong thing. There is also a rapidly growing number of mouse models of these disorders in which to test the idea. But until recently, the tools to make the test have not been there. We hope our methods will contribute to this important field.”
But while they are working toward that difficult goal, they can’t stop thinking about what the mouse is looking at. “Why in the world would mice need to develop cells to detect upward motion?” Sanes wonders. “It’s a great mystery. Maybe just fun… but a lot of things that start out as odd, quirky questions turn out to give important answers.”
Sanes and Meister’s co-authors on the Nature paper are In-Jung Kim, Yifeng Zhang, and Masahito Yamagata, all of Harvard’s Department of Molecular and Cellular Biology.