Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Double act: How a single molecule can attract and repel growing brain connections

11.08.2014

How can you find the same thing both attractive and repulsive? For growing neurons, the answer is in how they engage with it.

The findings, published online today in Neuron, stem from the 3D structure of Netrin-1 bound to one of the sensor molecules – receptors – the cell uses to detect it.


Depending on what receptors they have, axons (green) can be attracted (top) or repelled (bottom) by Netrin (grey). Credit:Dr. Lorenzo Finci (Harvard Medical School/Peking University) & Dr. Yan Zhang (Peking University).

The work, by scientists at the European Molecular Biology Laboratory (EMBL) in Hamburg, Germany, the Dana-Farber Cancer Institute affiliated to Harvard Medical School in Boston, the USA, and Peking University in Beijing, China, could also have implications for cancer treatment.

  “Although this is a challenging area for drug design, we found a mode of interaction that could be exploited to make cells respond to Netrin in a specific way, for instance to control proliferation or trigger programmed cell death,” says Rob Meijers, who led the work at EMBL.   Our brain’s ‘wiring’ is a set of protrusions that run from one neuron to another, like stretched-out arms.

As connections between neurons are established – in the developing brain and throughout life – each of these wires, or axons, grows out from a neuron and extends through the brain until it reaches its destination: the neuron it is connecting to. To choose its path, a growing axon senses and reacts to different molecules it encounters along the way.

One of these molecules, Netrin-1, posed an interesting puzzle: an axon can be both attracted to and repelled from this cue. The axon’s behaviour is determined by two types of receptor on its tip: DCC drives attraction, while UNC5 in combination with DCC drives repulsion.   When the scientists determined the 3D structure of Netrin-1 bound to DCC, they found the answer to this conundrum. The structure showed that Netrin-1 binds not to one, but to two DCC molecules.

But most surprisingly, it binds those two molecules in different ways.   “Normally a receptor and a signal are like lock-and-key, they have evolved to bind each other and are highly specific – and that’s what we see in one Netrin site,” says Meijers. “But the second is a very unusual binding site, which is not specific for DCC.”   Most of the second binding site does not connect directly to a receptor. Instead, it requires small molecules that act as middle-men.

These intermediary molecules seem to have a preference for UNC5, so if the axon has both UNC5 and DCC receptors, Netrin-1 will bind to one copy of UNC5 via those molecules and one copy of DCC at the DCC-specific site. This triggers a cascade of events inside the cell that ultimately drives the axon away from the source of Netrin-1, Yan Zhang’s lab at Peking University found.

The researchers surmise that, if an axon has only DCC receptors, each Netrin-1 molecule binds two DCC molecules, which results in the axon being attracted to Netrin-1.   “So by controlling whether or not UNC5 is present on its tip, an axon can switch from moving towards Netrin to moving away from it, weaving through the brain to establish the right connection,” says Jia-Huai Wang, who heads labs at Dana-Farber Cancer Institute and Peking University, and co-initiated the research.

Knowing how neurons switch from being attracted to Netrin to being repelled opens the door to devise ways of activating that switch in other cells that respond to Netrin cues, too. For instance, many cancer cells produce Netrin to attract growing blood vessels that bring them nourishment and allow the tumour to grow, so switching off that attraction could starve the tumour, or at least prevent it from growing.

On the other hand, when cancers metastasize they often stop being responsive to Netrin. In fact, the DCC receptor was first identified as a marker for an aggressive form of colon cancer, and DCC stands for ‘deleted in colorectal cancer’. Since colorectal cancer cells have no DCC, they are ‘immune’ to the programmed cell death that would normally follow once they move away from the lining of the gut and no longer have access to Netrin.

As a result, these tumour cells continue to move into the bloodstream, and metastasise to other tissues.   Meijers and colleagues are now investigating how other receptors bind to Netrin-1, and exactly how the intermediary molecules ‘choose’ their preferred receptor. The answers could one day enable researchers to steer a cell’s response to Netrin, ultimately changing its fate.

Published online in Neuron on 7 August 2014.DOI: http://dx.doi.org/10.1016/j.neuron.2014.07.010

For images and for more information please visit: http://www.embl.org/press/2014/140807_Hamburg

Policy regarding use EMBL press and picture releases including photographs, graphics and videos are copyrighted by EMBL. They may be freely reprinted and distributed for non-commercial use via print, broadcast and electronic media, provided that proper attribution to authors, photographers and designers is made.

Lena Raditsch Head of Communications European Molecular Biology Laboratory Meyerhofstraße 1 D-69117 Heidelberg Germany lena.raditsch@embl.de +49 62213878125 +4915114532784 www.embl.de

Lena Raditsch | EMBL Research News
Further information:
http://www.embl.de/aboutus/communication_outreach/media_relations/2014/140807_Hamburg/

Further reports about: Cancer EMBL Laboratory Molecular Netrin binds death receptor structure tumour

More articles from Life Sciences:

nachricht Protein scaffold
27.05.2015 | Okinawa Institute of Science and Technology (OIST) Graduate University

nachricht Seeing the action
27.05.2015 | University of California - Santa Barbara

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Advance in regenerative medicine

The only professorship in Germany to date, one master's programme, one laboratory with worldwide unique equipment and the corresponding research results: The University of Würzburg is leading in the field of biofabrication.

Paul Dalton is presently the only professor of biofabrication in Germany. About a year ago, the Australian researcher relocated to the Würzburg department for...

Im Focus: Basel Physicists Develop Efficient Method of Signal Transmission from Nanocomponents

Physicists have developed an innovative method that could enable the efficient use of nanocomponents in electronic circuits. To achieve this, they have developed a layout in which a nanocomponent is connected to two electrical conductors, which uncouple the electrical signal in a highly efficient manner. The scientists at the Department of Physics and the Swiss Nanoscience Institute at the University of Basel have published their results in the scientific journal “Nature Communications” together with their colleagues from ETH Zurich.

Electronic components are becoming smaller and smaller. Components measuring just a few nanometers – the size of around ten atoms – are already being produced...

Im Focus: IoT-based Advanced Automobile Parking Navigation System

Development and implementation of an advanced automobile parking navigation platform for parking services

To fulfill the requirements of the industry, PolyU researchers developed the Advanced Automobile Parking Navigation Platform, which includes smart devices,...

Im Focus: First electrical car ferry in the world in operation in Norway now

  • Siemens delivers electric propulsion system and charging stations with lithium-ion batteries charged from hydro power
  • Ferry only uses 150 kilowatt hours (kWh) per route and reduces cost of fuel by 60 percent
  • Milestone on the road to operating emission-free ferries

The world's first electrical car and passenger ferry powered by batteries has entered service in Norway. The ferry only uses 150 kWh per route, which...

Im Focus: Into the ice – RV Polarstern opens the arctic season by setting course for Spitsbergen

On Tuesday, 19 May 2015 the research icebreaker Polarstern will leave its home port in Bremerhaven, setting a course for the Arctic. Led by Dr Ilka Peeken from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI) a team of 53 researchers from 11 countries will investigate the effects of climate change in the Arctic, from the surface ice floes down to the seafloor.

RV Polarstern will enter the sea-ice zone north of Spitsbergen. Covering two shallow regions on their way to deeper waters, the scientists on board will focus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International symposium: trends in spatial analysis and modelling for a more sustainable land use

20.05.2015 | Event News

15th conference of the International Association of Colloid and Interface Scientists

18.05.2015 | Event News

EHFG 2015: Securing health in Europe. Balancing priorities, sharing responsibilities

12.05.2015 | Event News

 
Latest News

Researchers develop intelligent handheld robots

27.05.2015 | Power and Electrical Engineering

"Hidden" fragrance compound can cause contact allergy

27.05.2015 | Health and Medicine

Supernovas help 'clean' galaxies

27.05.2015 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>