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Heidelberg, 6 August 2010

Constant overlap

EMBL scientists identify molecular machinery that maintains important feature of the spindle

During cell division, microtubules emanating from each of the spindle poles meet and overlap in the spindle’s midzone. Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have uncovered the molecular mechanism that determines the extent of this overlap. In a study published today in Cell, they were able to reconstruct such anti-parallel microtubule overlaps in vitro, and identify two proteins which are sufficient to control the formation and size of this important spindle feature.

Thomas Surrey and his group at EMBL found that one protein, PRC1, bundles together microtubules coming from opposite ends of the cell, attaching them to each other. It then recruits a second protein, a molecular motor from the kinesin-4 subfamily, increasing its concentration in the spindle midzone. This motor walks along the overlapping microtubules like an officer on patrol, until it reaches one of the ends. When enough kinesin-4 molecules reach the end of the overlap, they inhibit the growth of microtubules there, thus keeping the overlap size constant without affecting microtubules elsewhere in the cell.

The spindle midzone plays an important role not only in helping to align the chromosomes in metaphase, but also in the final stages of cell division, when it drives the physical separation of the two daughter-cells. But between these two stages, the two ends of the spindle must move away from each other, to drag half the genetic material to each side of the dividing cell. At this point, if PRC1 and kinesin-4 had stopped microtubule growth permanently in the central part of the spindle, the overlap would become smaller and smaller, until eventually the spindle itself would collapse, jeopardising cell division. But Surrey and colleagues found that PRC1 and kinesin-4 control the overlap size in an adaptive manner. As the spindle stretches and the overlap between microtubules becomes smaller, the scientists posit, the inhibitory effect of kinesin-4 diminishes, allowing the microtubule ends to grow.

“Our findings show how molecules millionths of millimetres small can control the size of a structure about a thousand times larger than themselves,” Surrey concludes: “they help us to understand the fundamentals of cell division.”

Source Article
 

Bieling, P., Telley, I.A. & Surrey, T. A Minimal Midzone Protein Module Controls Formation and Length of Antiparallel Microtubule Overlaps. Cell, 6 August 2010.
 

Press Release 6 August 2010

Heidelberg, 4 August 2010

Supply and demand

EMBL scientists identify proteins that ensure iron balance

Most organisms need iron to survive, but too much iron is toxic, and can cause fatal organ failure. The same is true inside cells, where iron balance must also be maintained. In a study published today in Cell Metabolism, scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have discovered that a group of proteins named IRPs ensure that this iron balance is kept and as such are essential for cell survival. More specifically, they found that IRPs are required for the functioning of mitochondria, the cell’s energy factories.

Mitochondria need iron in order to function, but they also convert iron into other chemical forms used throughout the cell: iron sulphur clusters and haem – one of the building blocks of haemoglobin. Thanks to new mouse models they engineered, the EMBL scientists have been able to selectively shut down IRP function in specific cell types such as hepatocytes, liver cells that carry out multiple vital metabolic functions.

“Mice whose liver cells can’t produce IRPs die of liver failure a few days after birth,” says Bruno Galy, Staff Scientist in Matthias Hentze’s group at EMBL, who spearheaded the work: “The mitochondria in those cells have structural defects and don’t function properly, because they don’t have enough iron.”

Galy and colleagues found that in cells that cannot produce IRPs, the mechanisms for iron export and storage go into over-drive, while iron import is drastically reduced. This combination of factors leads to an iron shortage in the cell. As a consequence, the mitochondria don’t receive enough iron, so they can’t function properly, and can’t make enough haem and iron sulphur clusters available to the cell machinery that depends on them. In short, the role of IRPs is to ensure that there is enough iron available in the cell to sustain mitochondrial iron needs.

“We have indications that this is probably a general process by which most cells control their iron content and secure mitochondrial iron sufficiency” Hentze concludes.

This mechanism for regulating iron balance could be particularly important in cells with very high mitochondrial iron needs, such as red blood cell precursors that manufacture copious amounts of haem for oxygen transport. However, this may well be a double-edged sword. Indeed, there are situations in which mitochondria get iron but are not able to make use of it. The cell interprets this as a sign of mitochondrial iron insufficiency and responds by activating IRPs, which ultimately results in detrimental iron overloading of mitochondria. This may underlie the pathology of several diseases including inherited sideroblastic anaemias – in which cells are unable to incorporate iron into haemoglobin – or the neurodegenerative disorder Friedreich’s ataxia, which the EMBL scientists are currently investigating.

Source Article

Galy, B., Ferring-Appel, D.,  Sauer, S. W.,  Kaden, S., Lyoumi, S., Puy, H., Kölker, S., Gröne, H. J., & Hentze, M. W., Iron Regulatory Proteins Secure Mitochondrial Iron Sufficiency and Function, Cell Metabolism, 4 August 2010.

Press Release 4 August 2010

Heidelberg, 4 July 2010

Digital Embryo gains wings

Now possible to film development of fruit fly and of zebrafish’s eyes and brain

The scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, who ‘fathered’ the Digital Embryo have now given it wings, creating the Fly Digital Embryo. In work published today in Nature Methods, they were able to capture fruit fly development on film, and were the first to clearly record how a zebrafish’s eyes and midbrain are formed. The improved technique will also help to shed light on processes and organisms, which have so far been under-studied because they could not be followed under a microscope.

“Non-transparent samples like the fruit fly embryo scatter light, so the microscope picks up a mixture of in-focus and out-of-focus signal– good and bad information, if you like,” says Ernst Stelzer, whose group carried out the project at EMBL. “Our new technique enables us to discriminate between that good and bad information, so it allows us to record organisms which have so far been poorly studied, because of their unfortunate optical properties.”

Philipp Keller, who co-led and conducted the work, and Ernst Stelzer overcame the difficulties caused by thick, opaque samples, by shining patterns of light on them, instead of the usual continuous light sheet. This generates an image with alternating light and dark stripes, unless the light bounces off the sample and changes direction, in which case this stripy pattern will be blurred. By taking multiple images of different phases of the light pattern, and combining them, a computer can filter out the effects of scattered light and generate an accurate image of the sample, thus enabling scientists to record images that were previously unobtainable.By combining this approach with imaging along different angles, the scientists were able to obtain three-dimensional movies of the developing fruit fly embryo in spite of the fact that it is almost opaque.

The EMBL scientists were also able to extend their recordings of zebrafish development to an unprecedented level. They took around one million images to capture the first three days of zebrafish development from three different angles, generating films in which the formation of the animal’s eyes and midbrain are clearly visible.

“Of course, getting such good images is nice for the human observer, but it’s particularly crucial for computational analyses, like tracking cell movements and divisions as we do in the Digital Embryo,” says Philipp Keller, now at the Janelia Farm Research Campus of the Howard Hughes Medical Institute in Ashburn, VA, USA.

The work was done in collaboration with scientists at the University of Heidelberg, Germany and the Sloan-Kettering Institute in New York, USA.

All data, images and videos are freely available online, alongside the data from the digital embryo, at www.digital-embryo.org.

Source Article

Keller, P.J., Schmidt, A. D., Santella, A., Khairy, K., Bao, Z., Wittbrodt, J., Stelzer, E.H.K. Fast high-contrast imaging of animal development with scanned light sheet-based structured illumination microscopy. Nature Methods, 4 July 2010.

 Press Release 4 July 2010

Monterotondo, 31 May 2010

Making enough red blood cells

EMBL scientists identify molecules that ensure red blood cell production

Red blood cells, the delivery men that take oxygen to cells all around the body, have short lives. To keep enough of them in circulation, the human body produces around 2 million of these cells every second – even more in response to challenges like severe blood loss. In a study published today in the Journal of Experimental Medicine, scientists at the European Molecular Biology Laboratory (EMBL) in Monterotondo, Italy, and EMBL’s European Bioinformatics Institute (EMBL-EBI) in Hinxton, UK, have identified two small RNA molecules which ensure that enough red blood cells are produced efficiently, by fine-tuning a number of different genes involved in this process.

“A lot of the effort of blood cell formation, or haematopoiesis, goes into just keeping enough red blood cells in circulation” says Dónal O’Carroll, who led the work at EMBL Monterotondo: “We’ve identified two molecules that help to do so, and which are essential in challenging situations.”

To form red blood cells, large, round cells known as precursors have to become small and disc-shaped, like balls of plasticine squeezed between finger and thumb. In the process, they must also produce the large quantities of haemoglobin that will allow them to transport oxygen, and shrink and dispose of their nucleus. The EMBL scientists found that two microRNAs, called MiR144 and MiR451, control the final stages of this process.

O’Carroll and colleagues genetically engineered mice to have no MiR144 or MiR451. They found that such mice had defects in the final stages of red blood cell formation, but produced red blood cell precursors not only in the bone marrow, but also in large quantities in the spleen. By increasing the number of precursors, the mice compensated for the fact that a smaller percentage of those precursors matured into functional red blood cells, and thus were able to survive with only a mild anaemia.

“Under steady-state conditions, mice without MiR144 or MiR451 can just about produce enough red blood cells, but if you challenge them, by chemically inducing anaemia, most of them don’t survive, because in those conditions you just can’t live with inefficient red blood cell formation” O’Carroll explains.

O’Carroll and colleagues teamed up with Anton Enright’s group at EMBL-EBI, and used a sophisticated bioinformatics approach to understand how these microRNAs act. They found that of the two, MiR451 probably plays a key role in the process, and that it likely does so not by switching a single gene on or off, but by fine-tuning a multitude of genes involved in red blood cell formation.

These microRNA molecules have been conserved throughout vertebrate evolution. They are known to also be important for red blood cell formation in fish, and are likely to play a similar role in humans too. Thus, investigating their function further could help to understand how our own red blood cells are formed, and how defects in that process may lead to conditions such as anaemia.

Source Article

Rasmussen, K.D., Simmini, S., Abreu-Goodger, C., Bartonicek, N., Di Giacomo, M., Bilbao-Cortes, D., Horos, R., Von Lindern, M., Enright, A.J., & O’Carroll, D. The miR-144/451 locus is required for erythroid homeostasis, Journal of Experimental Medicine, Published online 31st May 2010.

 Press Release 31 Mai 2010

 Heidelberg, 2 May 2010

Tags on, tags off

EMBL scientists identify new regulatory protein complex with unexpected behaviour

During embryonic development, proteins called Polycomb group complexes turn genes off when and where their activity must not be present, preventing specialised tissues and organs from forming in the wrong places. They also play an important role in processes like stem cell differentiation and cancer. In a study published online today in Nature, scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, identified a new Polycomb group complex, and were surprised by how it acts.

Another Polycomb group complex was already known to silence genes by placing a chemical tag near them. Juerg Mueller and his group at EMBL found that the new Polycomb complex they discovered, PR-DUB, removes that same tag.

“Surprisingly, this new complex which takes the tag off seems to act in the same tissues and at the same developmental stages as the one that puts the tag on,” says Mueller, “and both opposing activities must occur to keep the gene silenced in our model organism, the fruit fly Drosophila.”

The reason for this unexpected behaviour is yet to be experimentally confirmed, but it may be a case of fine-tuning, with the newly-found complex ensuring that the chemical tagging is kept at its optimal level.

The human equivalent of PR-DUB is known to be a tumour-suppressor, and Mueller and colleagues discovered that, in test-tubes at least, it behaves the same way as the fruit fly complex, removing that same gene-silencing tag. Knowing how the complex acts in the fruit fly could help scientists uncover its function in the cells of mammals such as ourselves, and thus begin to shed light on its relation to cancer.

Press Release 2 Mai 2010

Hinxton, 8 April 2010

Variations on the genetic theme

EMBL-EBI researchers present global map of human gene expression

Just like members of an orchestra are active at different times although playing the same piece of music, every cell in our body contains the same genetic sequence but expresses this differently to give rise to cells and tissues with specialised properties.

By integrating gene expression data from an unprecedented variety of human tissue samples, Alvis Brazma and his team at the European Bioinformatics Institute, an outstation of the European Molecular Biology Laboratory (EMBL), and their collaborators have for the first time produced a global map of gene expression. The full analysis behind this unique view of the genetic activities determining our appearance, function and behaviour is published today in Nature Biotechnology.

The analysis used data collected from 163 laboratories worldwide involving 5,372 human samples from various tissues, cell types and diseases. Most transcriptomics experiments compare gene expression in only a few cell types or conditions and although technically challenging, integrating this data on a large-scale has created a new way for scientists to explore gene expression. The analysis is visualised as a map subdividing the human gene expression space into six distinct major groups or ‘continents’.

The continents emerged by grouping samples with similar gene expression signatures. This established the identity of the six groups: brain; muscle; hematopoietic (blood related); healthy and tumour solid tissues; cell lines derived from solid tissues; and partially differentiated cells. By visualising these subsets in 3D, comparisons can be made on the degree of similarity in the gene expression profiles on each grouping. For example, analysis of the continents showed that cell lines are usually more similar to each other than to their tissue of origin.  A new bioinformatics service allowing anyone to explore this expression map has been developed by the European Bioinformatics Institute as part of the ArrayExpress Gene Expression Atlas resource (www.ebi.ac.uk/gxa/).

Press Release 8 April 2010

Heidelberg, 18 March 2010

What makes us unique? Not only our genes

What counts is how genes are regulated, say scientists at EMBL and Yale

Once the human genome was sequenced in 2001, the hunt was on for the genes that make each of us unique. But scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and Yale and Stanford Universities in the USA, have found that we differ from each other mainly because of differences not in our genes, but in how they’re regulated – turned on or off, for instance. In a study published today in Science, they are the first to compare entire human genomes and determine which changes in the stretches of DNA that lie between genes make gene regulation vary from one person to the next. Their findings hail a new way of thinking about ourselves and our diseases.

The technological advances of the past decade have been so great that scientists can now obtain the genetic sequences – or genomes – of several people in a fraction of the time and for a fraction of the cost it took to determine that first human genome. Moreover, these advances now enable researchers to understand how genes are regulated in humans.

A group of scientists led by Jan Korbel at EMBL and Michael Snyder initially at Yale and now in Stanford were the first to compare individually sequenced human genomes to look for what caused differences in gene regulation amongst ten different people. They focused on non-coding regions – stretches of DNA that lie between genes and, unlike genes, don’t hold the instructions for producing proteins. These DNA sequences, which may vary from person to person, can act as anchors to which regulatory proteins, known as transcription factors, attach themselves to switch genes on or off.

Korbel, Snyder, and colleagues found that up to a quarter of all human genes are regulated differently in different people, more than there are genetic variations in genes themselves. The scientists found that many of these differences in how regulatory proteins act are due to changes in the DNA sequences they bind to. In some cases, such changes can be a difference in a single letter of the genetic code, while in others a large section of DNA may be altered. But surprisingly, they discovered even more variations could not be so easily explained. They reasoned that some of these seemingly inexplicable differences might arise if regulatory proteins didn’t act alone, but interacted with each other.

“We developed a new approach which enabled us to identify cases where a protein’s ability to turn a gene on or off can be affected by interactions with another protein anchored to a nearby area of the genome,” Korbel explains. “With it, we can begin to understand where such interactions happen, without having to study every single regulatory protein out there.”

The scientists found that even if different people have identical copies of a gene – for instance ORMDL3, a gene known to be involved in asthma in children – the way their cells regulate that gene can vary from person to person.

“Our findings may help change the way we think of ourselves, and of diseases”, Snyder concludes: “as well as looking for disease genes, we could start looking at how genes are regulated, and how individual variations in gene regulation could affect patients’ reactions.”

Finally, Korbel, Snyder and colleagues compared the information on humans with that from a chimpanzee, and found that with respect to gene regulation there seems to be almost as much variation between humans as between us and our primate cousins – a small margin in which may lie important clues both to how we evolved and to what makes us humans different from one another.

In a study published online in Nature yesterday, researchers led by Snyder in the USA and Lars Steinmetz at EMBL in Heidelberg have found that similar differences in gene regulation also occur in an organism which is much farther from us in the evolutionary tree: baker’s yeast.
 

Press Release 18 March 2010

Heidelberg, 31 January 2010

MicroRNA: a glimpse into the past

Small molecules give EMBL scientists bigger picture of animal evolution

The last ancestor we shared with worms, which roamed the seas around 600 million years ago, may already have had a sophisticated brain that released hormones into the blood and was connected to various sensory organs. The evidence comes not from a newly found fossil but from the study of microRNAs – small RNA molecules that regulate gene expression – in animals alive today. Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have discovered that these molecules are found in the exact same tissues in animals as diverse as sea anemones, worms, and humans, hinting at an early origin of these tissues in animal evolution. Their findings, published today in Nature, also open new avenues for studying the current functions of specific microRNAs.

Animals from different branches of the evolutionary tree – different lineages – possess specific microRNAs that evolved only in their lineage. But they also have microRNAs in common: ones which they inherited from their last common ancestor, and which have been conserved throughout animal evolution.

The EMBL scientists looked at the marine annelid Platynereis dumerilii, which is thought to have changed little over the past 600 million years. They visualised where these conserved microRNAs are expressed, and compared Platynereis with other animals. They found that in Platynereis these microRNAs are highly specific for certain tissues and cell types and, what is more, discovered that tissue specificity was conserved over hundreds of millions of years of evolutionary time.

The scientists reasoned that if an ancient microRNA is found in a specific part of the brain in one species and in a very similar location in another species, then this brain part probably already existed in the last common ancestor of those species. Thus, they were able to glean a glimpse of the past, an idea of some of the traits of the last common ancestor of worms and humans.

“By looking at where in the body different microRNAs evolved, we can build a picture of ancestors for which we have no fossils, and uncover traits that fossils simply cannot show us,” says Detlev Arendt, who headed the study: “But uncovering where these ancient microRNAs are expressed in animals from different branches of the evolutionary tree has so far been very challenging.”

“We found that annelids such as Platynereis and vertebrates such as ourselves share some microRNAs that are specific to the parts of the central nervous system that secrete hormones into the blood, and others that are restricted to other parts of the central or peripheral nervous systems, or to gut or musculature”, explains Foteini Christodoulou, who carried out most of the experimental work. “This means that our last common ancestor already had all these structures.”

Knowing where microRNAs were expressed in our ancestors could also help scientists understand the role of specific microRNA molecules today, as it gives them a clue of where to look.

“If a certain microRNA is known to have evolved in the gut, for instance, it is likely to still carry out a function there”, explains EMBL scientist Peer Bork, who also contributed to the study. Next, Arendt and colleagues would like to investigate the exact function of each of these conserved microRNAs – what genes they regulated, and what processes those genes were involved in – in an attempt to determine what their role might have been in the ancient past.
 

Press Release 31 January 2010

Heidelberg, 26 January 2010

How to shoot the messenger

EMBL scientists shed light on cellular communication systems involved in neurodegeneration, cancer and cardiovascular disease

Cells rely on a range of signalling systems to communicate with each other and to control their own internal workings. Scientists from the European Molecular Biology Laboratory (EMBL) in Hamburg, Germany, have now found a way to hack into a vital communications system, raising the possibility of developing new drugs to tackle disorders like neurodegeneration, cancer and cardiovascular disease. In a study published today in Science Signaling, they have pieced together the first snapshot of what two of the system’s components look like while interacting.

One way these signalling systems work is by triggering a flood of calcium ions inside the cell. These get picked up by a receiver, a protein called calmodulin which turns this calcium signal into action by switching various parts of the cell’s machinery on or off. Calmodulin regulates a set of proteins called kinases, each of which controls the activity of specific parts of the cell, thus altering the cell’s behaviour.

Using high-energy X-rays produced by the European Synchrotron Radiation Facility (ESRF) in Grenoble, France, and by the German Synchrotron Radiation Centre (DESY), in Hamburg, Germany, Matthias Wilmanns’ team at EMBL revealed the molecular structure of one of these kinases, a protein called Death-Associated Protein Kinase DAPK, when bound to calmodulin. The structure showed how calmodulin binds to a particular section of DAPK, switching the kinase on so that it can go and change the function of its targets. The team then worked out which of DAPK’s building blocks, or amino acids, were crucial for calmodulin to bind.

“Faulty versions of DAPK are involved in the development of some cancers,” says Wilmanns, “so we want to know more about how this protein functions to allow its better exploitation as an anti-cancer target.”

What’s more, DAPK has physical similarities to many of the other kinases controlled by calmodulin, meaning many of them are likely to interact with calmodulin in the same, or similar ways. Being able to see the three-dimensional structures of these proteins, how they clip together and alter each other’s behaviour means researchers can devise ways to manipulate this interaction with drugs.

“That will provide a platform to get into drug discovery,” says Wilmanns, adding, “obviously, this is the beginning of the story.” He is planning to do so in an ongoing collaboration with Adi Kimchi’s team at the Weizmann Institute in Israel and other groups from EMBL.

Press Release 26 January 2010

Heidelberg, 19 January 2010

Membrane-coat proteins: bacteria have them too

EMBL discovery could yield evolutionary insights and new model organism

Although they are present almost everywhere, on land and sea, a group of related bacteria in the superphylum Planctomycetes-Verrucomicrobia-Chlamydiae, or PVC, have remained in relative obscurity ever since they were first described about a decade ago. Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have discovered that these poorly-studied bacteria possess proteins thought to exist only in eukaryotes – organisms whose cells have a nucleus. Their findings, featured on the cover of today’s edition of PLoS Biology, could help to unravel part of the evolutionary history of eukaryotic cells such as our own.

In eukaryotes, the endomembrane system is a network of membrane-bound compartments which stores and transports material within the cell. These compartments, which include organelles such as the endoplasmic reticulum and the Golgi complex, also exchange portions of membrane with each other, by forming and absorbing vesicles. Scientists believed that membrane-bound compartments were unique to eukaryotic cells, and that membrane-coat proteins, which have a unique architecture and are associated with the endomembrane system, existed only in eukaryotes. Recently, however, membrane-bound compartments were observed in PVC bacteria.

In the new study, researchers in the group of Iain Mattaj, Director General of EMBL, are the first to provide molecular evidence that the coat proteins that shape the eukaryotic endomembrane system also exist in prokaryotes. Using a combination of bioinformatics, molecular biology and electron microscopy, the EMBL scientists found that proteins with the characteristic membrane-coat architecture also exist in members of the PVC group, but not in any other bacteria, in association with the membranes of subcellular compartments.

“Our findings provide unexpected clues as to how the endomembrane system of eukaryotes evolved,” says Damien Devos, who led the study, “and since they are relatively simple cells, these bacteria could be used as model organisms for studying how this system works.”

Press Release 19 January 2010

Heidelberg, 11 December 2009

The Battle of the Sexes

EMBL scientists uncover the gene responsible for keeping females female

Is it a boy or a girl? Expecting parents may be accustomed to this question, but contrary to what they may think, the answer doesn't depend solely on their child’s sex chromosomes. Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany and the Medical Research Council's National Institute for Medical Research (NIMR) at Mill Hill, UK discovered that if a specific gene located on a non-sex chromosome is turned off, cells in the ovaries of adult female mice turn into cells typically found in testes. Their study, published today in Cell, challenges the long-held assumption that the development of female traits is a default pathway. At the same time, it grants a valuable insight into how sex determination evolved.

In humans and most other mammals, an individual’s sex is determined by its sex chromosomes: females have two X chromosomes, males have one X and one Y. Scientists had long assumed that the female pathway – the development of ovaries and all the other traits that make a female – was a kind of default: if it had a gene called Sry, which is located on the Y chromosome, an embryo would develop into a male, if not, then the result would be a female. But in adult animals it is the male pathway that needs to be actively suppressed, as Mathias Treier and his team at EMBL discovered.

A gene called Foxl2, which is located on an autosome – a chromosome other than the sex chromosomes – and therefore present in both sexes, was known to play an important role in the female pathway, but its precise function remained elusive. To elucidate the matter, Treier and colleagues ablated, or ‘turned off’, this gene in the ovaries of adult female mice.

“We were surprised by the results,” says Treier: “we expected the mice to stop producing oocytes, but what happened was much more dramatic: somatic cells which support the developing egg took on the characteristics of the cells which usually support developing sperm, and the gender-specific hormone-producing cells also switched from a female to a male cell type.”

Thus, the scientists discovered that Foxl2 plays a crucial role in keeping female mice female.

Teaming up with the group of Robin Lovell-Badge at the NIMR, they were able to decipher together the underlying molecular mechanism. They showed that FOXL2 and oestrogen receptor act together by repressing a DNA element called TESCO that Lovell-Badge’s group had previously identified to regulate expression of the testes-promoting gene Sox9. Sox9 was known to function in the embryo to make the early gonads become testes rather than ovaries, but the new studies suggest that it can perform the same task in the adult. FOXL2 is therefore critical to keep Sox9 turned off in ovaries throughout life.

“As most vertebrates have Foxl2, oestrogen receptors and Sox9,” Lovell-Badge explains, “this mechanism for maintaining female traits probably appeared early on in the evolution of vertebrates, while Sry and the mammalian Y chromosome are relatively new inventions.”

These findings will have wide-ranging implications for reproductive medicine and may, for instance, help to treat sex differentiation disorders in children, for example where XY individuals develop as females or XX as males, and understand the masculinising effects of menopause on some women.

The study is discussed by author Mathias Treier in an online video in Cell’s ‘PaperFlicks’ series, which is available on YouTube. You can also watch the video by clicking the link at the top of this page.

Press Release 11 December 2009 

Monterotondo, 10 December 2009
 

From fruit fly wings to heart failure. Why Not(ch)?
 

EMBL scientists identify key signalling pathway for heart development and healing

Almost a century after it was discovered in fruit flies with notches in their wings, the Notch signalling pathway may come to play an important role in the recovery from heart attacks. In a study published today in Circulation Research, scientists at the European Molecular Biology Laboratory (EMBL) in Monterotondo, Italy, are the first to prove that this signalling pathway targets heart muscle cells and thus reveal its crucial role in heart development and repair.

The Notch pathway is a molecular mechanism through which cells communicate with each other. Scientists in Nadia Rosenthal’s group at EMBL used sophisticated genetic mouse models to uncover critical roles for this pathway in heart muscle cells. When they inactivated Notch specifically in the heart muscle precursor cells of early mouse embryos, the scientists discovered that the mice developed heart defects. Curiously, increasing Notch signalling in the heart muscle cells of older embryos had the same detrimental effect, uncovering different requirements for Notch as development proceeds.

“The cardiac malformations we observed are characteristic of Alagille syndrome, a human congenital disorder,” said first author Paschalis Kratsios,. “Therefore, our findings could help to explain the cardiac symptoms associated with Alagille syndrome and related forms of congenital heart disease.”

Intriguingly, the scientists were able to improve the cardiac function and survival rate of adult mice that had suffered heart attacks by re-activating Notch, suggesting new therapeutic approaches to help the heart recover from damage.

“Overall, these results highlight the importance of timing and context in biological communication mechanisms” Nadia Rosenthal concludes: “Our findings also lend support to the notion that, in certain situations, redeployment of embryonic signalling pathways could prove beneficial for tissue regeneration in the adult.”

Press Release 10 December 2009 

Heidelberg, 27 November 2009

First-ever blueprint of a minimal cell is more complex than expected

 EMBL and CRG scientists reveal what a self-sufficient cell can’t do without

What are the bare essentials of life, the indispensable ingredients required to produce a cell that can survive on its own? Can we describe the molecular anatomy of a cell, and understand how an entire organism functions as a system? These are just some of the questions that scientists in a partnership between the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and the Centre de Regulacio Genòmica (CRG) in Barcelona, Spain, set out to address. In three papers published back-to-back today in Science, they provide the first comprehensive picture of a minimal cell, based on an extensive quantitative study of the biology of the bacterium that causes atypical pneumonia, Mycoplasma pneumoniae. The study uncovers fascinating novelties relevant to bacterial biology and shows that even the simplest of cells is more complex than expected.

Mycoplasma pneumoniae is a small, single-cell bacterium that causes atypical pneumonia in humans. It is also one of the smallest prokaryotes – organisms whose cells have no nucleus – that don’t depend on a host’s cellular machinery to reproduce. This is why the six research groups which set out to characterize a minimal cell in a project headed by scientists Peer Bork, Anne-Claude Gavin and Luis Serrano chose M. pneumoniae as a model: it is complex enough to survive on its own, but small and, theoretically, simple enough to represent a minimal cell – and to enable a global analysis.

A network of research groups at EMBL’s Structural and Computational Biology Unit and CRG’s EMBL-CRG Systems Biology Partnership Unit approached the bacterium at three different levels. One team of scientists described M. pneumoniae’s transcriptome, identifying all the RNA molecules, or transcripts, produced from its DNA, under various environmental conditions. Another defined all the metabolic reactions that occurred in it, collectively known as its metabolome, under the same conditions. A third team identified every multi-protein complex the bacterium produced, thus characterising its proteome organisation.

“At all three levels, we found M. pneumoniae was more complex than we expected”, says Luis Serrano, co-initiator of the project at EMBL and now head of the Systems Biology Department at CRG.

When studying both its proteome and its metabolome, the scientists found many molecules were multifunctional, with metabolic enzymes catalysing multiple reactions, and other proteins each taking part in more than one protein complex. They also found that M. pneumoniae couples biological processes in space and time, with the pieces of cellular machinery involved in two consecutive steps in a biological process often being assembled together.

Remarkably, the regulation of this bacterium’s transcriptome is much more similar to that of eukaryotes – organisms whose cells have a nucleus – than previously thought. As in eukaryotes, a large proportion of the transcripts produced from M. pneumoniae’s DNA are not translated into proteins. And although its genes are arranged in groups as is typical of bacteria, M. pneumoniae doesn’t always transcribe all the genes in a group together, but can selectively express or repress individual genes within each group.

Unlike that of other, larger, bacteria, M. pneumoniae’s metabolism doesn’t appear to be geared towards multiplying as quickly as possible, perhaps because of its pathogenic lifestyle. Another surprise was the fact that, although it has a very small genome, this bacterium is incredibly flexible and readily adjusts its metabolism to drastic changes in environmental conditions. This adaptability and its underlying regulatory mechanisms mean M. pneumoniae has the potential to evolve quickly, and all the above are features it also shares with other, more evolved organisms.

“The key lies in these shared features”, explains Anne-Claude Gavin, an EMBL group leader who headed the study of the bacterium’s proteome: “Those are the things that not even the simplest organism can do without and that have remained untouched by millions of years of evolution – the bare essentials of life”.
This study required a wide range of expertise, to understand M. pneumoniae’s molecular organisation at such different scales and integrate all the resulting information into a comprehensive picture of how the whole organism functions as a system – an approach called systems biology.

“Within EMBL’s Structural and Computational Biology Unit we have a unique combination of methods, and we pooled them all together for this project”, says Peer Bork, joint head of the unit, co-initiator of the project, and responsible for the computational analysis. “In partnership with the CRG group we thus could build a complete overall picture based on detailed studies at very different levels.” Bork was recently awarded the Royal Society and Académie des Sciences Microsoft Award for the advancement of science using computational methods. Serrano was recently awarded a European Research Council Senior grant. 

Press Release 27 November 2009 

 Heidelberg, 8 November 2009

Drought resistance explained

Structural study at EMBL reveals how plants respond to water shortages

Much as adrenaline coursing through our veins drives our body’s reactions to stress, the plant hormone abscisic acid (ABA) is behind plants’ responses to stressful situations such as drought, but how it does so has been a mystery for years. Scientists at the European Molecular Biology Laboratory (EMBL) in Grenoble, France, and the Consejo Superior de Investigaciones Cientificas (CSIC) in Valencia, Spain discovered that the key lies in the structure of a protein called PYR1 and how it interacts with the hormone. Their study, published online today in Nature, could open up new approaches to increasing crops’ resistance to water shortage.

Under normal conditions, proteins called PP2Cs inhibit the ABA pathway, but when a plant is subjected to drought, the concentration of ABA in its cells increases. This removes the brake from the pathway, allowing the signal for drought response to be carried through the plant’s cells. This turns specific genes on or off, triggering mechanisms for increasing water uptake and storage, and decreasing water loss. But ABA does not interact directly with PP2Cs, so how does it cause them to be inhibited? Recent studies had indicated that the members of a family of 14 proteins might each act as middle-men, but how those proteins detected ABA and inhibited PP2Cs remained a mystery – until now.

A group of scientists headed by José Antonio Márquez from EMBL Grenoble and Pedro Luis Rodriguez from CSIC looked at one member of this family, a protein called PYR1. When they used X-ray crystallography to determine its 3-dimensional structure, the scientists found that the protein looks like a hand. In the absence of ABA, the hand remains open, but when ABA is present it nestles in the palm of the PYR1 hand, which closes over the hormone as if holding a ball, thereby enabling a PP2C molecule to sit on top of the folded fingers. As these features seem to be conserved across most members of this protein family, these findings confirm the family as the main ABA receptors. Moreover, they elucidate how the whole process of stress response starts: by binding to PYR1, ABA causes it to hijack PP2C molecules, which are therefore not available to block the stress response.

“If you treat plants with ABA before a drought occurs, they take all their water-saving measures before the drought actually hits, so they are more prepared, and more likely to survive that water shortage – they become more tolerant to drought”, Rodriguez explains.  “The problem so far”, Márquez adds, “has been that ABA is very difficult – and expensive – to produce. But thanks to this structural biology approach, we now know what ABA interacts with and how, and this can help to find other molecules with the same effect but which can be feasibly produced and applied."

To determine the structure of PYR1, the scientists made use of the infrastructure of the Partnership for Structural Biology, including EMBL Grenoble’s high-throughput crystallisation facilities and the beamlines at the European Synchrotron Radiation Facility, located in the same campus as EMBL Grenoble.

Press Release 8 November 2009

Heidelberg, 1 October 2009

From foe to friend: mosquitoes that transmit malaria may help fight the disease

EMBL scientists identify gene behind malaria-resistant mosquitoes

For many years, the mosquitoes that transmit malaria to humans were seen as public enemies, and campaigns to eradicate the disease focused on eliminating the mosquitoes. But, as a study published today in Science shows, the mosquitoes can also be our allies in the fight against this common foe, which kills almost one million people a year and heavily impairs the economies of affected countries. In this study, researchers at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and the Institut National de la Santé et de la Recherche Médicale (INSERM) in Strasbourg, France, discovered that variations in a single gene affect mosquitoes’ ability to resist infection by the malaria parasite.

“Malaria parasites must spend part of their lives inside mosquitoes and another part inside humans, so by learning how mosquitoes resist malaria, we may find new tools for controlling its transmission to humans in endemic areas”, says Stephanie Blandin from INSERM, who carried out the research at EMBL in collaboration with Lars Steinmetz’s group and with Rui Wang-Sattler (now at the Helmholtz Zentrum in Munich, Germany).

The scientists looked for clues in the genome – the whole DNA – of Anopheles gambiae mosquitoes, a major carrier of the parasite that causes the most severe form of human malaria in Africa. They focused on the mosquitoes’ resistance to a commonly used model organism: Plasmodium berghei, a parasite that causes malaria in rodents.

When they compared the genomes of mosquitoes that could resist this infection to those of mosquitoes that couldn’t, the scientists discovered that the major difference lies in a single section of one chromosome. Of the roughly 975 genes contained in this section of DNA, one in particular appears to play an important role in determining a mosquito’s resistance to malaria. This gene, called TEP1, encodes a protein which was known to bind to and promote the killing of Plasmodium berghei malaria parasites in the mosquito’s midgut, and the scientists discovered that their strain of resistant mosquitoes had a form, or allele, of TEP1, that was different from those found in non-resistant (or susceptible) strains.

To investigate whether this difference in alleles caused the variation in the mosquitoes’ resistance to malaria, the scientists developed a new technique, reciprocal allele-specific RNA interference, inspired by one Steinmetz’s group had previously created to study yeast. “This was a breakthrough, because the new technique is applicable to many different organisms”, says Steinmetz. “It extends the power we gained in yeast: we can go from a whole region of DNA to the actual causative gene – a feat rarely achievable in complex organisms”. The technique enables scientists to identify exactly which allele is behind a specific trait. They produced individual mosquitoes that had one TEP1 allele from the resistant strain and another from a susceptible strain, and then “turned off” – or silenced – one or other of these alleles. The result: silencing different alleles produced mosquitoes with different degrees of resistance to malaria, meaning that an individual mosquito’s resistance to the malaria parasite depends largely on which form(s) of this one gene it carries.

Although this study focused on the parasite that causes malaria in rodents, there is evidence that this gene may also be involved in the mosquitoes’ immune response to human malaria – a connection the scientists are exploring, and which they believe may help to make malaria eradication programs more effective.

Press Release 1 October 2009

Monterotondo, 13 September 2009