Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

A Second Career for a Growth Factor Receptor: Keeping Nerve Axons on Target

15.09.2008
Neurons constituting the optic nerve wire up to the brain in a highly dynamic way. Cell bodies in the developing retina sprout processes, called axons, which extend toward visual centers in the brain, lured by attractive cues and making U-turns when they take the wrong path. How they find targets so accurately is a central question of neuroscience today.

Using the mouse visual system, a team of Salk Institute for Biological Studies investigators led by Dennis O’Leary, Ph.D., identified an unanticipated factor that helps keep retinal axons from going astray. They report in the Sept. 11 issue of Neuron that p75, a protein previously known to regulate whether neurons live or die, leads a double life as an axon guidance protein.

“Historically, we thought that factors that mediate cell survival and those controlling axon guidance were part of two separate processes,” says O’Leary, a professor in the Molecular Neurobiology Laboratory, “But in this study we show a direct interaction between these two systems.”

Collaborating with Kuo-Fen Lee, Ph.D., professor in the Clayton Foundation Laboratories for Peptide Biology, the O’Leary team observed a defect in mice genetically engineered to lack p75. Through their synaptic connections, retinal axons develop a two-dimensional map of the retina in their targets in the brain. In the mice lacking p75, retinal axons stopped short of their final target and formed a map that was shifted forward in the superior colliculus, a major visual center in the brain.

Such a defect in p75-null mice was puzzling: researchers have studied p75 for decades and found it associated with activities as varied as neuronal growth, survival, and degeneration. Axonal migration was not among them.

Todd McLaughlin, Ph.D., a senior research associate in the lab and co-first author, says that insight came in a eureka moment: “We realized that what we were observing in these mice was similar to what would happen if you deleted a gene called ephrin-A from the retina.”

Unlike p75, ephrin-A was a well-characterized sender and receiver of axon guidance signals, but it lacked appendages normally seen on proteins controlling axon migration. p75, however, displayed those elements, suggesting that the proteins could pair up — one receiving the migration signal and the other transmitting it.

The research team then turned to biochemical analyses and with the added expertise of Tsung-Chang Sung, Ph.D., a research associate in Dr. Lee’s lab, obtained evidence that supported this hypothesis. The group found that ephrin-A and p75 complexes in axonal membranes and showed that when activated they could generate the signals required to guide axons and develop their map in the brain.

But the clincher was the “stripe assay,” a classical screen for guidance molecules that repel growing axons. In it, an immature neuron is placed on a microscopic running track, just as it starts to develop an axon. When flanking lanes are carpeted with repellant factors, the sprouting axon bursts from the block but remains in its lane like a well-coached runner, avoiding neighboring tracks.

Constructing tracks made from the repulsive factor sensed by ephrin-A, the researchers confirmed that axons from normal retinal neurons stayed in their lanes when flanked by the repellant. But neurons from mice lacking p75 were unreceptive to repulsive cues: when placed on the track their axons meandered all over the field, crossing lanes and running down repellant-covered stripes.

Why retinal neurons missed the target in the p75-minus mice became clear: they lacked the cellular machinery to respond to critical repellant signals encountered in the brain and stopped migrating prematurely.

Among its myriad functions, p75’s new role is a critical one. “Repulsion is probably the dominant force in axon guidance and a stronger influence than attraction,” explains McLaughlin, noting that providing axons with a lot of options is not the way to build a brain. “Attraction is like finding the best seat in an empty movie theater, but repulsion is like picking the lone empty seat in a full theater.”

“We have shown that ephrin-A cannot transduce an intracellular signal by itself and instead requires the co-receptor p75,” summarizes Yoo-Shick Lim, Ph.D., a postdoctoral fellow in the O’Leary lab and co-first author. “This interaction could operate in numerous events in neural development.”

O’Leary believes that identifying mechanisms underlying developmental events is fundamental to understanding the basis of any biological disorder. “These studies establish that two distinct molecular systems, neurotrophins and axon guidance, both critical for neural development directly collaborate to develop neural connectivity.

Findings such as these lend critical insight into how one might repair damage to the nervous system due to genetic defects, tumors or wounds to the brain or spinal cord,” he says. “We hope one day to be able to repair these defects and get cells to form functional connections again.”

Alicia Santiago, Ph.D., formerly of the O’Leary lab, also contributed to the study. Salk professor Tony Hunter and Sourav Ghosh, a former postdoctoral fellow in the Hunter lab, helped with preliminary biochemical experiments. Funding was from a grant from the National Eye Institute and from the Joseph Alexander Foundation.

For information on commercialization of this technology, please contact Mike White, Ph.D., Office of Technology Management (mwhite@salk.edu, 858-453-4100 x 1703).

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.

Mike White | Newswise Science News
Further information:
http://www.salk.edu

More articles from Life Sciences:

nachricht How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH

nachricht A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Quantum thermometer or optical refrigerator?

23.06.2017 | Physics and Astronomy

A 100-year-old physics problem has been solved at EPFL

23.06.2017 | Physics and Astronomy

Equipping form with function

23.06.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>