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Stem cells - Pancreatic endocrine progenitors adopt single fate.
Pancreatic islets contain several different types of hormone (endocrine) producing cells, and their damage can lead to disease, such as diabetes.
During embryonic development, all pancreatic endocrine progenitor cells express the transcription factor Ngn3.
However, whether individual Ngn3+ progenitors give rise to multiple endocrine cell types or only to one remained unknown.
Pedro Herrera’s team published the answer in the November 2009 issue of Development.
Using a genetic system called MADM, the researchers generated transgenic mosaic mice in which they traced the fate of individual Ngn3+ progenitor cells.
They found that at birth, each of them had turned into a single endocrine cell.
These findings suggest that the Ngn3+ progenitors are heterogeneous, as they are unipotent but give rise to multiple cell types, and showcase the potential of MADM for investigating cell fate specification events in vivo at the single-cell level.
• Publication in Development
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The Hox complex - An interview with Denis Duboule.
“Science is arguably a serious matter, but why should the presentation of science be so boring?”
This is part of the answer given by the director of our NCCR when he was asked whether he has a mischievous streak.
Jokes, puns and spicy titles are embedded in some of Denis Duboule’s articles, notes the scientist Michael Richardson in an interview released in June 2009.
The publication retraces the career of Denis Duboule, “one of the most influential and highly-cited scientists in developmental biology”.
This colorful interview, peppered with glimpses at Denis’ multifaceted personality, describes the major steps involved in the construction of the Hox edifice and his key role in its achievement.
• Publication in The International Journal of Developmental Biology
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Stem cells - The “Hedgehog” pathway is essential for the development and growth of colon cancers.
Mice harbouring human colon carcinomas have been successfully cured with treatments targeting the “Hedgehog-Gli” pathway, according to a study published in EMBO Molecular Medicine in August 2009.
Ariel Ruiz i Altaba’s team has discovered that the activation of this pathway is essential for tumour growth, recurrence, metastasis, as well as stem cell survival and expansion.
The group succeeded in blocking the growth and dissemination of the cancer with cyclopamine, a plant extract that inhibits the “Hedgehog-Gli” cascade, without noticeable side effects.
This pathway thus represents a target for novel anti-tumor therapies against so far incurable forms of colon cancer in distant organs, such as the liver.
Ariel Ruiz i Altaba is currently identifying and testing new molecules targeting the “Hedgehog-Gli” function.
Cyclopamine is indeed very difficult to produce and more potent molecules may exist.
The scientists’ start-up Phistem, created in June 2009, provides the frame for the development of candidate therapies.
• Details on UNIGE website (In French)
• Publication in EMBO Molecular Medicine
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Biological nanotools - Identifying specific neuronal circuits and a new retinal cell type.
The new classes of nanotools developed earlier this year by Botond Roska’s team allow to observe the activity of many neurons simultaneously in different brain circuits.
The scientists have engineered genetically modified viruses that can move across neurons that are connected and leave a fluorescent trail.
The different neuronal cell types involved within a path, as well as their diverse connections, are thus displayed in the colors of the rainbow.
Roska’s group then combined these nanotools with other techniques in order to identify circuits activated by a particular visual impression.
The retina contains 50-60 neuronal cell types that respond to different stimuli and are interconnected in a variety of circuits that process the visual input.
In the 2nd August 2009 issue of Nature Neuroscience, the scientists describe how they have constituted a “genetic address book for retinal cell types” by screening and analysing transgenic mice lines with selectively marked cell types.
In parallel, the researchers discovered a new cell type in the retina that performs a very specific visual function related to the detection of approaching objects.
The study, presented in Nature Neuroscience on September 6th 2009, also describes the identification of the network of neurons in which the cell type is involved.
Combining different sophisticated approaches, they have demonstrated how the overall response is fine tuned by the different constituents of the network.
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Section of a transgenic mouse retina stained with various dyes. Green cells express the green fluorescent protein (GFP).
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• Publications in Nature Neuroscience: September 2009 and October 2009
• Cover of Nature Neuroscience, September 2009
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Anti-cholesterol - A potential treatment of liver pathologies induced by estrogens.
An exaggerated production of estrogens can provoke hepatic inflammation and toxicity.
The cholestase that may result from it is the most frequent pathology of the liver occurring during pregnancy.
This serious complication could in the future be treated with a specific anti-cholesterol drug, according to the study performed by Walter Wahli’s team.
The article published in the Journal of Clinical Investigation on September 1st 2009 describes the molecular mechanisms of hepatic protection induced by this therapy in mice.
The professor exposes the role played by the transcription factor PPARα, that exerts a range of repressive actions on hepatic genes involved in steroid metabolism and immunity.
However, some of these effects are much more emphasized, or even unique, in female mice with respect to their male counterparts.
• Details in UNIL press release (PDF; 1 page, 94.2 KB; in French)
• Publication in the Journal of Clinical Investigation
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Apoptosis - A new type of development program for head regeneration is demonstrated in hydra.
“Hydrae seem to be immortal”. This observation is the driving force of research in Brigitte Galliot’s lab, which is involved in the pilot project “stem cells and regeneration”.
The scientist investigates stem cell function and cell plasticity in this small and fascinating animal, champion of regeneration.
Her group has discovered a new type of development program used by the polyp to reconstitute its head after amputation.
The process involves massive apoptosis (self-destruction) of superficial cells, which will orchestrate the cellular responses of reconstruction.
This molecular dialogue, described in the 18th of August 2009 issue of Developmental Cell, may constitute a common mechanism of initiating regeneration, also valid in humans.
Two-headed hydra - After amputation, the induction of apoptosis at the level of the future foot induces the formation of a head in this region.
• Details on UNIGE website (In French)
• Publication in Developmental Cell
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Antisense RNA - Certain genes can be silenced in several ways.
Many cells are able to silence specific genes by a mechanism called RNA interference (RNAi).
But how do cells which are missing the RNAi machinery, such as yeast, manage to accomplish such a task ?
Françoise Stutz’s team has unveiled in 2007 a hitherto unknown process used by those micro-organisms to inhibit the expression of specific genes, such as PHO84, via antisense RNA production.
A study published by this group in the 1st of July 2009 issue of Genes & Development adds new elements to these results.
The scientist describes another means used by yeast to repress the PHO84 gene.
This process, set off when the cell receives an additional copy of this gene, also involves the synthesis of antisense RNA.
However, the latter uses a different pathway, with the participation of new “molecular actors”.
These studies show that RNA is able to repress gene expression via multiple pathways.
• Publication in Genes & Development
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Architect genes - Our body plan contains instructions in filigree.
Architect genes are essential for coordinating body patterning during embryonic development.
Research projects led by Denis Duboule during the last twenty years have shed light on how these tiny conductors direct construction operations.
Until now, the processes modulating these genes themselves remained an enigma.
The professor and his collaborator Natalia Soshnikova provide now key answers in the 5th June 2009 edition of Science.
Their study demonstrates that architect gene expression is influenced by epigenetic mechanisms that modify DNA without affecting its sequence.
These processes are reversed as these genes become successively mobilised.
• Details in press release (PDF; 2 pages, 146 KB) or on UNIGE website (In French)
• Publication in Science
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Circadian system - MicroRNAs grease the cell’s circadian clockwork.
Most of our cells possess an internal clock, a group of genes displaying a cyclic expression pattern that reaches a peak once a day.
A large number of circadian genes are expressed by organs such as the liver, whose activity needs to be precisely regulated over the course of the day.
Ueli Schibler’s team reveals that an important regulator of this molecular oscillator is a specific microRNA.
The latter belongs to a class of small RNA molecules that regulate the production of proteins in our cells.
Thus far, little was known about their function within the circadian clockwork.
The study published in the 1st June 2009 edition of Genes & Development, fills in this important gap.
• Details in press release (PDF; 2 pages, 125 KB) or on UNIGE website (In French)
• Publication in Genes & Development
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Neuronal connections - Regulation of synaptic specificity by a mechanism of avoidance.
In order to be able to function correctly, nerve cells must be connected to each other in highly precise patterns.
The flow and direction of information through neuronal circuits are ensured by the presence of synapses, the contact points between two nerve cells.
It is thought that these precise connectivity patterns emerge during development, but mechanisms of how precision is controlled remain elusive.
Silvia Arber’s team describes in Nature on May 6 2009 the molecular logic underlying synaptic specificity in the nervous system.
In other terms, why certain nerve cells establish synapses with each other while others fail to do so.
The scientists have identified a critical recognition system in sensory-motor circuits in mice.
They have found motor neuron pools that express cell surface molecules named Sema3e, which are recognized by receptors called plexin D1, present on adjacent sensory neurons.
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Three synaptic contact sites (white) between sensory neuron terminals (turquoise) and a motor neuron (pink).
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Interestingly, this recognition program is based on repellent signalling.
Expression of Sema3e and plexin D1 on pairs of possible synaptic partners prevents the formation of synapses between them, thus redirecting the flow of information to a different path.
• Details on Biozentrum website
• Publication in Nature
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A nose that detects pathogens - Discovery of a new family of receptors of the olfactory system.
Mammals rely heavily on olfaction to interact adequately with each other and with their environment.
In mice, pheromones and odours are perceived via receptors located on specific neurons in the nose.
Until now, four classes of receptors have been identified.
Ivan Rodriguez’ team just discovered a new family of sensors.
This study, published in Nature on April 22nd 2009, also reveals that these receptors detect molecules associated with inflammatory or pathogenic states.
• Details on UNIGE website (In French)
• Publication in Nature
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Ribosomes - Identification of a mechanism that controls the fabrication of these tiny cellular factories.
Ribosomes are one of the growth driving forces of the cell, both in normal and pathological conditions.
Researchers are thus interested in the mechanisms that control the production of these organelles within the cell.
The team of David Shore and Robbie Loewith uncovers a regulation loop that modulates the construction of these tiny cellular “factories” in response to local constraints.
This molecular dialogue, described in the Molecular Cell edition of March 27th 2009, probably allows optimising ribosome production in various growth and stress conditions.
• Details on UNIGE website (In French)
• Publication in Molecular Cell
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Architect genes - Two major phases of regulation are involved in the complex dialogue between Hox genes.
Hox genes, which are responsible for the distribution of our structures during embryonic development, are clustered in one site on the chromosome.
These “architect” genes are transcribed sequentially, in both time and space, following their relative positions within their genomic clusters.
The team of Denis Duboule further unveils the complex regulatory relationships involved in Hox gene expression, in the 6th March 2009 issue of PLoS Genetics.
Their study shows that the spatial organization of expression domains does not directly depend upon the timing of activation as was previously suggested.
This uncoupling coincides with the existence of two major phases of regulation involving both global and local influences.
These results indicate that different types of collinearities are not necessarily related, either in function, or in their evolutionary histories.
• Publication in PLoS Genetics
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Bidirectional promoters - New data change our view of how a genome is transcribed.
Only 2% of the human genome contains instructions for making proteins, yet most of our DNA is transcribed into RNA, for unknown reasons.
This is also the case in yeast, which produce a large number of RNAs whose function remains mysterious.
Part of the latter, which are called Cryptic Unstable Transcripts (CUTs), are immediately destroyed after being synthesized.
In order to understand where and how these unstable transcripts are produced, Françoise Stutz participated in establishing a complete repertoire of RNAs expressed in yeast.
The study resulting from the collaboration with Lars Steinmetz’s team, published in the 25th of January 2009 edition of Nature, shows that the transcription of a CUT RNA starts at the same promoter as the one for a coding RNA, but on the opposite strand.
“This means that the same promoter can regulate the initiation of transcription either on one strand and in one direction, or on the other and in the opposite direction”, explains the scientist.
These results demonstrate the intrinsic bidirectional nature of eukaryotic promoters.
The detailed genomic map of CUTs revealed that they derive from extremely widespread and very well defined transcription units and do not result from unspecific transcriptional “noise”.
Whether these non coding RNAs display functionality, as regulators of gene expression for instance, remains to be determined.
• Publication in Nature
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Biological nanotools - Watching the activity of brain circuits.
A major challenge in understanding the function of different brain circuits is that they are usually intermingled and perform parallel computations.
To identify the unknown synaptic connections between the billions of neurons that make up the nervous system, Botond Roska’s team has developed new classes of nanotools.
These are genetically engineered viruses that can move across neurons, but only between those that are connected.
Each time the virus passes through a neuron it lights up a “fluorescent light bulb”.
The group made three types of transsynaptic viruses.
The first class was engineered with differentially colored “bulbs” such that neural circuits could be lit up with all the shades of the rainbow.
The second class of viruses brought a small genetic clock to each infected cell in the circuit so the elapsed time after the virus entry could be recorded.
The third class had the most intelligent nanotools. These viruses turned on a special fluorescent bulb in each neuron but only when the neuron is active.
Using these tools, described the 4th of January 2009 in Nature Methods, researchers will be able to “watch” the activity of many neurons simultaneously in identified, connected neurons of different brain circuits.
Viral transsynaptic nanotools light up different brain circuits in various colors.
• Publication in Nature Methods
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