Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Salk researchers discover that stem cell marker regulates synapse formation

31.01.2011
Among stem cell biologists there are few better-known proteins than nestin, whose very presence in an immature cell identifies it as a "stem cell," such as a neural stem cell. As helpful as this is to researchers, until now no one knew which purpose nestin serves in a cell.

In a study published in the Jan. 30, 2011, advance online edition of Nature Neuroscience, Salk Institute of Biological Studies investigators led by Kuo-Fen Lee, PhD., show that nestin has reason for being in a completely different cell type--muscle tissue. There, it regulates formation of the so-called neuromuscular junction, the contact point between muscle cells and "their" motor neurons.

Knowing this not only deepens our understanding of signaling mechanisms connecting brain to muscle, but could aid future attempts to strengthen those connections in cases of neuromuscular disease or spinal cord injury.

"Nestin was a very well known molecule but no one knew what it did in vivo," says Lee, a professor in the Clayton Foundation Laboratories for Peptide Biology. "Ours is the first study to show that it actually has a physiological function."

Previously, researchers knew that as the neuromuscular junction formed in a developing embryo, so-called positive factors cemented connections between incoming nerve fibers and dense clusters of neurotransmitter receptors facing them on muscle fibers. However, in a 2005 Neuron paper Lee defined a counterbalancing factor--the protein cdk5--that whisked away, or dispersed, superfluous muscle receptors lying outside the contact zone, or synapse, so only the most efficient connections were maintained.

The current study addresses how cdk5, which catalytically adds chemical phosphate groups to target proteins, eliminates useless "extrasynaptic" connections. Reasoning that cdk5 must act by chemically modifying a second protein, Jiefei Yang, PhD., a post-doctoral fellow in the Lee lab and the current study's first author, took on the task of finding its accomplice.

He began by eliminating prime suspects in the plethora of proteins found on the muscle side of the synapse. "At the beginning it was like shooting in the dark because cdk5 has so many potential targets at the neuromuscular junction," says Yang. After eliminating the obvious candidates, the team finally considered nestin, based on evidence that cdk5 can phosphorylate nestin in some tissues.

To analyze nestin, the group employed mice in which the positive, synapse-stabilizing factor--known as agrin--had been genetically eliminated. As predicted, microscopic examination of diaphragm muscle tissue in agrin mutant mice showed a complete loss of dense receptor clusters that would mark a mature synapse, meaning that without the agrin "cement," synapse-dispersing activity had swept away the clusters.

However, when agrin mutant mice were administered an RNA reagent that literally knocks out nestin expression, the group made a dramatic finding: the pattern of receptor clusters on diaphragm muscle reappeared, reminiscent of synapses of a normal mouse--meaning that getting rid of nestin allows synapses to proceed even in the absence of the stabilizing glue.

"This in vivo experiment represents a critical genetic finding," explains Lee. "Later, we determined that nestin's basic function is to recruit cdk5 and its co-activators to the muscle membrane, leading to cdk5 activation and initiating the dispersion process." Additional experiments confirmed that nestin is expressed on the muscle side of the neuromuscular junction, in other words, in the "right" place, and that nestin phosphorylation is required for its newfound function.

Lee believes that information revealed by the study could enhance development of tissue replacement therapies. "Currently, in efforts to devise therapies for motor neuron disease or spinal cord injury there is a lot of focus is on how to make neurons survive," he says. "That is important, but we also need to know how to properly form a synapse. If we cannot, the neuromuscular junction won't function correctly."

Yang, who studied animal models of motor neuron disease while a graduate student at USC, agrees. "One long-term goal of this study is to identify ways to inhibit cdk5/nestin," he says. "That could slow synapse deterioration in neuromuscular junction diseases, such as ALS (Lou Gehrig's Disease) or spinal motor atrophy, in which you have an imbalance of positive and negative signals. One approach is to boost positive signaling, but another is to inhibit negative signaling in an effort to slow disease progression."

Other authors of the study include Bertha Dominguez, Fred de Winter, and Thomas Gould in the Lee lab, and John Eriksson at Åbo Akademi University in Turku, Finland.

Support for the work came from the National Institutes of Health, the Muscular Dystrophy Association, and the Research Institute of the Åbo Akademi University.

About the Salk Institute for Biological Studies:

The Salk Institute for Biological Studies is one of the world's preeminent basic research institutions, where internationally renowned faculty probe fundamental life science questions in a unique, collaborative, and creative environment. Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer's, diabetes and infectious diseases by studying neuroscience, genetics, cell and plant biology, and related disciplines.

Faculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark.

Gina Kirchweger | EurekAlert!
Further information:
http://www.salk.edu

More articles from Life Sciences:

nachricht Researchers identify how bacterium survives in oxygen-poor environments
22.11.2017 | Columbia University

nachricht Researchers discover specific tumor environment that triggers cells to metastasize
22.11.2017 | University of California - San Diego

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

UCLA engineers use deep learning to reconstruct holograms and improve optical microscopy

22.11.2017 | Medical Engineering

Watching atoms move in hybrid perovskite crystals reveals clues to improving solar cells

22.11.2017 | Materials Sciences

New study points the way to therapy for rare cancer that targets the young

22.11.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>