{"id":1442,"date":"2014-08-08T13:54:25","date_gmt":"2014-08-08T11:54:25","guid":{"rendered":"http:\/\/news.embl.de\/?p=1442"},"modified":"2024-11-14T16:32:12","modified_gmt":"2024-11-14T15:32:12","slug":"1408_neurons","status":"publish","type":"post","link":"https:\/\/www.embl.org\/news\/science\/1408_neurons\/","title":{"rendered":"International connections"},"content":{"rendered":"\n

How is it possible that, in this seemingly random network of connections, nothing goes wrong? What invisible hand steers the neurons safely to their destination? Through a collaboration spanning several years, three continents and several close calls with airport security, Rob Meijers, group leader from EMBL Hamburg<\/a>, and collaborators have determined the structure of an unusual protein complex that plays an important role in guiding neurons.<\/p>\n\n\n\n

Triggered attractions<\/h3>\n\n\n\n

At the tip of growing  axons sits a ‘growth cone’, a fan-shaped structure with finger-like extensions. Receptors expressed on the cone recognise signals from the cell\u2019s surroundings, which they interpret into path-finding instructions, like a dog following a scent trail. These signals, or guidance cues, trigger an \u2018attract\u2019 or \u2018repel\u2019 response. One of the four major families of guidance cue proteins is netrin \u2013 from the Sanskrit word \u201cNetr\u201d meaning \u201cone who guides\u201d \u2013 a small but unique family of proteins that can trigger attraction and repulsion. How one molecule performs these contradictory push-and-pull functions has long been a mystery.<\/p>\n\n\n\n

Netrins have undergone very few changes during evolution and are conserved across the entire animal kingdom. Meijers and colleagues studied netrin-1 in complex with one of its receptors, DCC, which together trigger an attraction. The structural data, published in Neuron<\/em><\/a>, show that a single netrin-1 molecule can bind with two molecules of DCC simultaneously. \u201cOne binding site is specific to DCC,\u201d explains Meijers, \u201cbut the second is not. It is a generic binding site that can also accept other receptors.\u201d Exchanging DCC for another receptor in the non-specific site switches the neuron\u2019s response from attraction to repulsion, changing the protruding axon\u2019s direction of growth.<\/p>\n\n\n\n

\"Depending
Depending on what receptors they have, axons (green) can be attracted (left) or repelled (right) by netrin (grey). Credit: Lorenzo Finci (Harvard Medical School\/Peking University) & Yan Zhang (Peking University)<\/figcaption><\/figure><\/div>\n\n\n\n

Boston-Hamburg-Beijing<\/h3>\n\n\n\n

The finding is the result of an ambitious research project that accrued many thousands of frequent-flyer miles for the scientists and their samples. \u201cIt has been an extraordinary journey,\u201d says Lorenzo Finci, the postdoc who worked on the project with Meijers, and who globe-trotted between three of the world\u2019s top science institutes \u2013 and into several nerve-wracking situations.<\/p>\n\n\n\n

Finci was recruited by Jia-huai Wang from the Dana Farber Cancer Institute in Boston, to work in a newly established lab at Peking University. After receiving a short-term EMBO fellowship to fund a three-month stay in Germany, he arrived in Hamburg in November: \u201cMy first Thanksgiving outside of the US,\u201d he says. \u201cI didn\u2019t know where to find a traditional Thanksgiving turkey, so instead I celebrated with a burger, which I\u2019d heard were famous in Hamburg!\u201d During a cold winter, Lorenzo worked together with Nina Kr\u00fcger from Rob\u2019s group to work out how to purify netrin and, crucially, how to put it together with DCC.<\/p>\n\n\n\n

Straight to the beam<\/h3>\n\n\n\n

Once Finci\u2019s fellowship ended and he returned to China, the project became even more international, which proved as stimulating as it was stressful. \u201cEverything works on a 24 hour cycle,\u201d says Meijers, \u201cWhen I wake up, China has already been working for six hours. By the time I go to bed, Boston has another six hours worth of data to hand back to Beijing.\u201d Transporting samples was also problematic: \u201cGetting liquid samples in and out of China is impossible by mail.\u201d Finci took advantage of a family trip to Turkey, enlisting his cousins to race him through Istanbul traffic so that he could ship samples to Hamburg overnight.<\/p>\n\n\n\n

Getting liquid samples in and out of China is impossible by mail.<\/p><\/blockquote>\n\n\n\n

Meijers and his group got to work, and within a week crystals had formed \u2013 but was it the sought after DCC-netrin complex? \u201cI received an excited email that it was,\u201d Finci recalls. \u201cI called my supervisor, Jia-huai Wang, maybe 50 times before he finally called me back and I shared the good news!\u201d Meijers stresses the advantage of having immediate access to the beamlines and sample characterisation facilities at the PETRA III synchrotron ring on the Deutsches Elektronen-Synchrotron (DESY) campus. \u201cWe crystallised the protein complex using our on-site facility<\/a> the same day. Normally, you sacrifice a few crystals before finding the ideal conditions, but those crystals went straight to the beamline and the first one diffracted successfully\u201d.<\/p>\n\n\n\n

\"Meijers,
Meijers, centre, with collaborators Finci and Jie Zhang at EMBL Hamburg. PHOTO: EMBL\/Rob Meijers<\/figcaption><\/figure><\/div>\n\n\n\n

Binding site negotiations<\/h3>\n\n\n\n

Later that week, the group noticed there were actually two binding sites on netrin, and decided to have a friendly bet on which site was more physiologically relevant. \u201cSite 1 would be celebrated with Dutch-brewed Heineken, site 2 with Tsingtao,\u201d says Finci.<\/p>\n\n\n\n

Characterising the two binding sites meant more trips for Finci. \u201cHe acted as a ‘mule’, travelling back and forth between Beijing and Hamburg 10 times,\u201d says Meijers. \u201cAfter one 13-hour trip from Beijing to Hamburg, the customs agent called me over,\u201d says Finci. \u201cI declared the bag\u2019s contents, and showed them the paperwork. Two hours later, I had an audience and was being investigated by five agents and two dogs!\u201d EMBL Hamburg\u2019s administrators came to the rescue, rushing over new paperwork with official EMBL seals. On returning to Beijing, this time with netrin in hand, the same thing happened. \u201cI learned two important lessons: to carry documentation with impressive seals, and a box of chocolates for my friends the customs agents.\u201d<\/p>\n\n\n\n

Most protein binding sites have a ‘lock and key’ mechanism \u2013 this second non-specific binding site is unusual<\/p><\/blockquote>\n\n\n\n

It turned out that both binding sites are important, so rather than beer, the teams celebrated with wine and a Peking Duck dinner when Meijers visited Beijing. \u201cMost protein binding sites have a ‘lock and key’ mechanism,\u201d explains Meijers. \u201cThis second non-specific binding site is unusual: it is positively charged, as are the receptors, so normally they would repel each other, like equivalent magnet poles.\u201d Instead, it seems that sulphate ions sit in the binding site and negotiate which receptor is received. \u201cThese negatively charged ions are organised in such a way that they can also be replaced by certain sugar-like molecules, called heparan sulphates,\u201d adds Meijers. \u201cWe know that deactivating sugar molecules confuses neuronal wiring \u2013 to make a link that suggests sugars and small molecules are important in selecting receptors could be relevant for rational drug design.\u201d<\/p>\n\n\n\n

Beyond neurobiology<\/h3>\n\n\n\n

Although their work has concentrated on the field of neurobiology, the results have possible applications in the field of cancer biology. Many cancer cells produce netrin to attract blood vessels that nourish them and help them grow. Interrupting this netrin supply could starve the tumour, or at least prevent it from growing. DCC stands for \u2019Deleted in Colorectal Cancer\u2018 and its absence seems to result in uncontrolled cell growth and tumour metastasis. \u201cMaybe now that we know more about how DCC and netrin-1 work, we can attempt to influence cell growth and stop tumour metastasis in its tracks,\u201d says Meijers.<\/p>\n","protected":false},"excerpt":{"rendered":"

How a single molecule can attract and repel growing brain connections<\/p>\n","protected":false},"author":18,"featured_media":1443,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[2,17591],"tags":[29,48,53,100,1748,35],"embl_taxonomy":[],"class_list":["post-1442","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-science","category-science-technology","tag-crystallography","tag-facility","tag-hamburg","tag-meijers","tag-press-release","tag-structural-biology"],"acf":{"article_intro":"

During the development of the human brain, hundreds of billions of nerve cells in the nervous system are making new connections. Despite this unimaginable amount of wiring, the main component of our nervous system, the neuron, always seems to know exactly where to go, and extends nerve fibres \u2013 or axons \u2013 towards their final target with precision and determination.<\/p>\n","related_links":[{"link_description":"Jia-Huai Wang Laboratory, Harvard Medical School","link_url":"http:\/\/wang.dfci.harvard.edu\/"},{"link_description":"Meijers group reveals how a molecular switch enables viruses to destroy C.diff bacteria, 24 July 2014 ","link_url":"http:\/\/news.embl.de\/science\/1407_cdiff\/"},{"link_description":"Deutsches Elektronen-Synchrotron (DESY), Hamburg","link_url":"http:\/\/www.desy.de\/index_eng.html"}],"article_sources":[{"source_description":"

Finci, L.I., et al. <\/em>Published online in\u00a0Neuron,\u00a0<\/em>7 August 2014. DOI:\u00a010.1016\/j.neuron.2014.07.010<\/p>\n","source_link_url":"http:\/\/www.sciencedirect.com\/science\/article\/pii\/S0896627314006217"}],"vf_locked":false,"featured":false,"color":"#007B53","show_featured_image":false,"in_this_article":false,"youtube_url":"","mp4_url":"","video_caption":"","translations":false,"press_contact":"EMBL Generic"},"embl_taxonomy_terms":[],"yoast_head":"\nInternational connections | EMBL<\/title>\n<meta name=\"description\" content=\"How a single molecule can attract and repel growing brain connections\" \/>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.embl.org\/news\/science\/1408_neurons\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"International connections | EMBL\" \/>\n<meta property=\"og:description\" content=\"How a single molecule can attract and repel growing brain connections\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.embl.org\/news\/science\/1408_neurons\/\" \/>\n<meta property=\"og:site_name\" content=\"EMBL\" \/>\n<meta property=\"article:publisher\" content=\"https:\/\/www.facebook.com\/embl.org\/\" \/>\n<meta property=\"article:published_time\" content=\"2014-08-08T11:54:25+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2024-11-14T15:32:12+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2014\/08\/1408_neurons1.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"620\" \/>\n\t<meta property=\"og:image:height\" content=\"380\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"Rosemary Wilson\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:creator\" content=\"@rawilson80\" \/>\n<meta name=\"twitter:site\" content=\"@embl\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Rosemary Wilson\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"6 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"NewsArticle\",\"@id\":\"https:\/\/www.embl.org\/news\/science\/1408_neurons\/#article\",\"isPartOf\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/1408_neurons\/\"},\"author\":{\"name\":\"Rosemary Wilson\",\"@id\":\"https:\/\/www.embl.org\/news\/#\/schema\/person\/bb5e57a6c6c5c3b33a6a40b2d4c96e40\"},\"headline\":\"International connections\",\"datePublished\":\"2014-08-08T11:54:25+00:00\",\"dateModified\":\"2024-11-14T15:32:12+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/1408_neurons\/\"},\"wordCount\":1157,\"publisher\":{\"@id\":\"https:\/\/www.embl.org\/news\/#organization\"},\"image\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/1408_neurons\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2014\/08\/1408_neurons1.jpg\",\"keywords\":[\"crystallography\",\"facility\",\"hamburg\",\"meijers\",\"press release\",\"structural biology\"],\"articleSection\":[\"Science\",\"Science & Technology\"],\"inLanguage\":\"en-US\"},{\"@type\":\"WebPage\",\"@id\":\"https:\/\/www.embl.org\/news\/science\/1408_neurons\/\",\"url\":\"https:\/\/www.embl.org\/news\/science\/1408_neurons\/\",\"name\":\"International connections | EMBL\",\"isPartOf\":{\"@id\":\"https:\/\/www.embl.org\/news\/#website\"},\"primaryImageOfPage\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/1408_neurons\/#primaryimage\"},\"image\":{\"@id\":\"https:\/\/www.embl.org\/news\/science\/1408_neurons\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2014\/08\/1408_neurons1.jpg\",\"datePublished\":\"2014-08-08T11:54:25+00:00\",\"dateModified\":\"2024-11-14T15:32:12+00:00\",\"description\":\"How a single molecule can attract and repel growing brain connections\",\"inLanguage\":\"en-US\",\"potentialAction\":[{\"@type\":\"ReadAction\",\"target\":[\"https:\/\/www.embl.org\/news\/science\/1408_neurons\/\"]}]},{\"@type\":\"ImageObject\",\"inLanguage\":\"en-US\",\"@id\":\"https:\/\/www.embl.org\/news\/science\/1408_neurons\/#primaryimage\",\"url\":\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2014\/08\/1408_neurons1.jpg\",\"contentUrl\":\"https:\/\/www.embl.org\/news\/wp-content\/uploads\/2014\/08\/1408_neurons1.jpg\",\"width\":620,\"height\":380,\"caption\":\"Netrin-1 (orange\/pink) can bind to two copies of DCC (green). 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