Scientists map signalling networks that control neuron function

Washington, January 29 : Researchers at the University of California, San Diego (UCSD) have mapped thousands of neuronal proteins to discover how they connect into complex signalling networks that guide neuron function.

The researchers say that their work may help advance the understanding of brain development, neurodegenerative diseases, and spinal cord regeneration.

During the study, they used quantitative mass spectrometry, computational software and bioinformatics to match the proteins to their cellular functions.

Richard Klemke, professor of pathology at UCSD School of Medicine and the Moores UCSD Cancer Center, says that his team designed a new technology that enabled them to isolate and purify neurites - long membrane extensions from the neuron that give rise to axons or dendrites.

He says that the new technology opens the door to understanding how neurites form and differentiate to regenerate neuronal connections, and give rise to a functioning network.

The study, to be published in the online edition of Proceedings of the National Academy of Sciences, also led to the discovery of how two key signalling molecules are regulated by a complex protein network that controls neurite outgrowth.

According to the researchers, the formation of neurites, a process called neuritogenesis, is the first step in the differentiation of neurons, the basic information cells of the central nervous system.

"Understanding how neurites form is crucial, as these structures give rise to the specialized axons and dendrites which relay sensory input and enable us to see, hear, taste, reason and dream," said Klemke.

Neurons regenerate by sending out one or several long, thin neurites that ultimately differentiate into axons, which primarily receive signals, or dendrites, primarily involved in sending out signals.

Such long, branch-like protrusions have a specialized sensory structure called a growth cone that probes the extracellular environment to find its way, and determine which direction the neurite should move in order to hook up with other neurites that will also differentiate into axons and dendrites.

The UCSD team is studying a huge information grid made by the neural signalling network of dendrites and axons in order to discover how neurons connect properly, and regenerate to maintain proper wiring of the brain.

They believe that understanding the role that neuritogenesis plays in the regeneration of nerve connections damaged by diseases like Alzheimer's, Parkinson's or other neurogenerative diseases is an important component of mapping the signalling network.

"Our primary goal is to identify unique proteins that cause the neurite to sprout and differentiate. We also want to understand the underlying signals that guide neurite formation and migration in response to directional cues," said Klemke.

The research team has identified a complex network of enriched proteins, called GEFs and GAPs, which control neuritogenesis by modulating signalling.

"This signaling provides external guidance cues to mechanical mechanisms inside the cell that make the neurite go forward, turn, or reverse direction. Understanding how the thousands of neurite proteins work in concert may someday help us guide neurites to the right place in the body to regenerate and reverse the impact of neural degenerative diseases or help facilitate spinal cord healing after injury," Klemke said.

The researchers developed a unique microporous filter technology to separate the neurite from the cell body of the neuron, called the soma. They say that the ability to slice millions of neurons into their soma and neurite components opened the door to using mass spectrometry, a tool able to identify the thousands of proteins that uniquely compose the two structures.

Using information gleaned from published work, the researchers were then able to predict the function of most of the neurite proteins, which enabled them to construct a blueprint of how the thousands of proteins work together to facilitate neurite formation.

ANI