S. Lawrence Zipursky to receive 2015 Louisa Gross Horwitz Prize from Columbia University

Columbia University will award the 2015 Louisa Gross Horwitz Prize to S. Lawrence Zipursky, PhD, for discovering a molecular identification system that helps neurons to navigate and wire the brain. Zipursky is a professor of biological chemistry at the University of California, Los Angeles (UCLA) and a Howard Hughes Medical Institute (HHMI) investigator. The Horwitz Prize, first awarded in 1967, is Columbia University's top honor for achievement in biological and biochemical research. Forty-three Horwitz Prize awardees have won Nobel Prizes.

"Dr. Zipursky's research has helped illuminate one of science's biggest mysteries: how do our brains work, and how did they develop such incredible complexity?" said Lee Goldman, MD, Harold and Margaret Hatch Professor of the University, dean of the Faculties of Health Sciences and Medicine, and chief executive of Columbia University Medical Center.

"Forming a deep understanding of how our brains are wired is a vital step in revealing how complex neurological disorders develop. For this reason, Dr. Zipursky's work is invaluable," added Gerard Karsenty, MD, PhD, chair of the Horwitz Prize Committee, and chair of the department of genetics and development at Columbia University Medical Center.

How an organism behaves and makes decisions is largely determined by how the cells in its nervous system are wired together. Since starting his lab at UCLA in 1985, Zipursky's research has focused on identifying genes that guide the formation of connections between neurons into circuits. From this search, Zipursky's team discovered a gene called Dscam, a fruit fly gene related to the human Down Syndrome Cell Adhesion Molecule (DSCAM) gene, which helps neurons choose the right paths to take as they extend through the developing nervous system.

Zipursky's lab found that Dscam harnesses a special genetic process called "alternative splicing," which combines different stretches of code from the same gene. This mechanism allows Dscam to produce over 38,000 different versions of the same protein. This finding led Zipursky's group to propose that the protein diversity encoded inside the Dscam gene could underlie complex wiring decisions in the nervous system.

Precisely how Dscam accomplished this feat was unknown. Zipursky's team showed that rather than directly instructing nerve cells how to wire together, Dscam helps a neuron distinguish between its own branches and the branches of other neurons. Each neuron chooses to display a specific set of Dscam variants on its surface, with the result that each nerve cell has a unique identity. In effect, Dscam is the nervous system's molecular ID tag.

Zipursky and colleagues showed that Dscam molecular barcoding is the basis for a process called "self-avoidance" in which neurons guide themselves through the wiring process by pushing away their own branches. The diverse ID tags provided by Dscam ensure that this repulsion happens only between branches from the same cell. This process of self-recognition followed by repulsion sculpts the complex branching pattern of neurons, and prevents neurons from making connections to themselves.

These discoveries, along with research from others, reveal how different processes work together to wire the brain. Cells leave trails of molecules for neurons to follow in the developing brain, deploy guide cells to chaperone wandering branches, or--as Zipursky discovered--use genetic name badges that allow neurons to distinguish between one another. These molecular mechanisms all weave together elegantly to organize a complex neural architecture.

"The Horwitz Prize is awarded annually for research that has transformed our fundamental thinking about how biology works," says Michael Purdy, PhD, executive vice president for research at Columbia University. "Dr. Zipursky's work is an excellent example of this as it is an important step toward revealing the mysteries of the most complex object in the known universe: the brain."