Corporate Banner
Satellite Banner
Scientific Community
Become a Member | Sign in
Home>News>This Article

Double Act: How a Single Molecule Can Attract and Repel Growing Brain Connections

Published: Saturday, August 09, 2014
Last Updated: Saturday, August 09, 2014
Bookmark and Share
The 3D structure of Netrin-1 bound to DCC shows Netrin-1 binds to two DCC molecules in different ways.

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

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 metastasize 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.

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,700+ scientific posters on ePosters
  • More than 3,800+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Finding Links and Missing Genes
A catalogue of large-scale genetic changes around the world.
Tuesday, October 06, 2015
Ages Apart
Multifaceted approach measured how brain and liver age differently.
Saturday, September 19, 2015
Cancer by Remote-Control
Overlooked DNA shuffling drives deadly paediatric brain tumour.
Tuesday, June 24, 2014
Wired for Change
First steps of gene regulation evolution revealed.
Monday, August 05, 2013
Rigged to Explode?
Inherited mutation links exploding chromosomes to cancer.
Wednesday, April 11, 2012
The Human Genome’s Breaking Points
Comprehensive catalogue uncovers genetic sequence of large-scale differences between human genomes.
Wednesday, February 16, 2011
EMBL Scientists Uncover Counterpart of Cerebral Cortex in Marine Worms
Findings give an idea of what the most ancient higher brain centres looked like, and what our distant ancestors used them for.
Friday, September 03, 2010
Making Enough Red Blood Cells
EMBL scientists identify molecules that ensure red blood cell production.
Monday, June 14, 2010
EMBL-EBI Researchers Present Global Map of Human Gene Expression
The full analysis behind the view of the genetic activities determining our appearance, function and behavior is published in Nature Biotechnology.
Thursday, April 08, 2010
New Training and Conference Centre for the Life Sciences at EMBL in Heidelberg
The new Center will form a central European platform where scientists from across the world can meet to exchange ideas and their best practices.
Thursday, March 11, 2010
EMBL Scientists Present Genetic Catalogue of Our Gut Flora
A study shows that, at 3.3 million, microbial genes in our gut outnumber previous estimates for the whole of the human body.
Monday, March 08, 2010
EMBL Scientists Uncover the Gene Responsible for Keeping Females Female
Study, published in Cell, challenges the long-held assumption that the development of female traits is a default pathway.
Friday, December 11, 2009
EMBL Scientists Take New Approach to Predict Gene Expression
The new approach enables the accurate prediction of when and where different CRMs will be active.
Wednesday, November 18, 2009
Scientists Identify Cholesterol-Regulating Genes
EMBL researchers identified 20 genes that are involved in the process of regulating cholesterol levels in the body.
Monday, July 13, 2009
European Centre of Excellence for Mouse Biology Celebrates its 10th Anniversary
Scientists investigating basic research topics have generated mouse models of over 20 different human diseases over the past 10 years.
Wednesday, July 01, 2009
Scientific News
Gene Editing Could Enable Pig-To-Human Organ Transplant
The largest number of simultaneous gene edits ever accomplished in the genome could help bridge the gap between organ transplant scarcity and the countless patients who need them.
Antioxidants Cause Malignant Melanoma to Metastasize Faster
Fresh research at Sahlgrenska Academy has found that antioxidants can double the rate of melanoma metastasis in mice.
UC San Diego Team Up with Illumina to Speed-Read Your Microbiome
Data analysis app accelerates studies aimed at using microbes to predict, diagnose and treat human diseases.
Paving the Way for Diamonds to Trace Early Cancers
Researchers from the University of Sydney reveal how nanoscale 'diamonds' can light up early-stage cancers in MRI scans.
Researchers Develop Classification Model for Cancers Caused by KRAS
Most frequently mutated cancer gene help oncologists choose more effective cancer therapies.
Chromosomal Chaos
Penn study forms basis for future precision medicine approaches for Sezary syndrome
Shaking Up the Foundations of Epigenetics
Researchers at the Centre for Genomic Regulation (CRG) and the University of Barcelona (UB) published a study that challenges some of the current beliefs about epigenetics.
Genetic Defences of Bacteria Don’t Aid Antibiotic Resistance
Genetic responses to the stresses caused by antibiotics don’t help bacteria to evolve a resistance to the medications, according to a new study by Oxford University researchers.
Tolerant Immune System Increases Cancer Risk
Researchers have found that individuals with high immunoCRIT ratios may have an increased risk of developing certain cancers.
Developing a Gel that Mimics Human Breast for Cancer Research
Scientists at the Universities of Manchester and Nottingham have been funded to develop a gel that will match many of the biological structures of human breast tissue, to advance cancer research and reduce animal testing.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,700+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos