ENS - Départment de biologie

Régis Ferrière, lauréat du prix de la Recherche 2013 en mathématiques

Marie Embs — 2015-02-25T11:17:28Z

Le magazine La Recherche, créé il y a plus de 40 ans, s'efforce de rendre accessible au plus grand nombre les travaux de recherches publiés à travers la planète. S'adressant à un lectorat d'experts passionnés autant que d'amateurs éclairés, La Recherche reste ouvert à toutes les sciences et à toutes les technologies dans leurs dimensions de découverte et d'approfondissement des savoirs nouveaux.

C'est pourquoi le magazine a créé il y a neuf ans le Prix La Recherche, remis chaque année afin de suivre au plus près les avancées de la science.

Plus d'informations ici

Vincent Colot, lauréat du grand prix de l'Académie des Sciences Charles-Léopold Mayer 2013

Marie Embs — 2015-02-25T11:15:11Z

http://www.academie-sciences.fr/activite/prix/laureat_gp2013.pdf

The Dynamic Synapse

Marie Embs — 2015-02-25T11:11:58Z

The constant dynamic movement of synapses and their components has emerged in the last decades as a key feature of synaptic transmission and its plasticity. Intramolecular protein movements drive conformation changes important to transduce transmitter binding into signaling. Constant cytoskeletal rearrangements power synapse shape movements. Vesicular trafficking at the pre- and postsynapse underlies transmitter release and receptor traffic between the cell surface and intracellular compartments, respectively. Receptor movement in the plane of the plasma membrane by thermally powered Brownian diffusion movement and reversible trapping by receptor-scaffold interactions has emerged as the main mechanism to dynamically organize the synaptic membrane in nanoscale domains. We will discuss here the different conceptual and methodological advances that have led to a rethinking of the synapse as an organelle whose function is tightly linked to its dynamic organization.

Neuron, Volume 80, Issue 3, 691-703, 30 October 2013

A naturally occurring single amino acid insertion rewires transcriptional regulation by Glucocorticoid receptor isoforms

Marie Embs — 2015-02-25T11:10:51Z

In addition to guiding proteins to defined genomic loci, DNA can act as an allosteric ligand that influences protein structure and activity. Here we compared genome-wide binding, transcriptional regulation and, using NMR, the conformation of two glucocorticoid receptor (GR) isoforms that differ by a single amino acid insertion in the lever arm, a domain that adopts DNA sequence-specific conformations. We show that these isoforms differentially regulate gene expression levels through two mechanisms : differential DNA binding and altered communication between GR domains. Our studies suggest a versatile role for DNA in both modulating GR activity and also in directing the use of GR isoforms. We propose that the lever arm is "fulcrum" for bidirectional allosteric signaling, conferring conformational changes in the DNA reading head that influence DNA sequence selectivity, as well as changes in the dimerization domain that connect functionally with remote regulatory surfaces, thereby influencing which genes are regulated and the magnitude of their regulation.

Proc Natl Acad Sci U S A. 2013 Oct 14.

Cytosolic Transmitter Concentration Regulates Vesicle Cycling at Hippocampal GABAergic Terminals

Marie Embs — 2015-02-25T11:10:04Z

Sustained synaptic transmission requires vesicle recycling and refilling with transmitter, two processes considered to proceed independently. Contrary to this assumption, we show here that depletion of cytosolic transmitter at GABAergic synapses reversibly reduces the number of recycling vesicles. Using paired recordings in hippocampal cultures, we show that repetitive activity causes two phases of reduction of the postsynaptic response. The first involves the classical depletion of the readily releasable and recycling pools, while the second reflects impairment of vesicle filling as GABA is consumed, since it can only be reversed by uptake of GABA or its precursors, glutamate or glutamine. Surprisingly, this second phase is associated with reduced quantal release, a faster depression rate and lower FM5-95 labeling, suggesting that the size of the cycling vesicular pool is regulated by cytosolic transmitter availability. Regulation of vesicular cycling may represent a general mechanism of presynaptic plasticity, matching synaptic release to transmitter supply.

Neuron 80,143-158

A deletion polymorphism in the Caenorhabditis elegans RIG-I homolog disables viral RNA dicing and antiviral immunity

Marie Embs — 2015-02-25T11:09:15Z

RNA interference defends against viral infection in plant and animal cells. The
nematode Caenorhabditis elegans and its natural pathogen, the positive-strand RNA virus Orsay,have recently emerged as a new animal model of host-virus interaction. Using a genome-wide association study in C. elegans wild populations and quantitative trait locus mapping, we identify a 159 base-pair deletion in the conserved drh-1 gene (encoding a RIG-I-like helicase) as a major determinant of viral sensitivity. We show that DRH-1 is required for the initiation of an antiviral RNAi pathway and the generation of virus-derived siRNAs (viRNAs). In mammals, RIG-I-domain containing proteins trigger an interferon-based innate immunity pathway in response to RNA virus infection. Our work in C. elegans demonstrates that the RIG-I domain has an ancient role in viral recognition. We propose that RIG-I acts as modular viral recognition factor that couples viral recognition to different effector pathways including RNAi and interferon responses.

Ashe et al. eLife 2013 ;2:e00994. DOI : 10.7554/eLife.00994

NMDA receptor subunit diversity : impact on receptor properties, synaptic plasticity and disease

Marie Embs — 2015-02-25T11:08:28Z

Receptors (NMDARs) are glutamate-gated ion channels and are crucial for neuronal communication. NMDARs form tetrameric complexes that consist of several homologous subunits. The subunit composition of NMDARs is plastic, resulting in a large number of receptor subtypes. As each receptor subtype has distinct biophysical, pharmacological and signalling properties, there is great interest in determining whether individual subtypes carry out specific functions in the CNS in both normal and pathological conditions. Here, we review the effects of subunit composition on NMDAR properties, synaptic plasticity and cellular mechanisms implicated in neuropsychiatric disorders. Understanding the rules and roles of NMDAR diversity could provide new therapeutic strategies against dysfunctions of glutamatergic transmission.

Nat Rev Neurosci. 2013 Jun ;14(6):383-400

Role of Pleiotropy in the Evolution of a Cryptic Developmental Variation in Caenorhabditis elegans

Marie Embs — 2015-02-25T11:07:16Z

Figure 1. Cryptic variation in C. elegans vulval cell fate patterning.
( C ) Schematic representation of cryptic variation. Genetic variation between wild genotypes leads to variation in intermediate developmental processes such as signaling pathway activities, while the final system output (here vulval cell fates) remains invariant.

Professeur à l'ENS depuis 2010, Marie-Anne Félix vient d'intégrer l'IBENS avec son équipe de recherche

PLoS Biol. 2012 Jan ;10(1):e1001230. Epub 2012 Jan 3.

Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission.

Marie Embs — 2015-02-25T11:06:28Z

Fine control of neuronal activity is crucial to rapidly adjust to subtle changes of the environment. This fine-tuning was thought to be purely neuronal until the discovery that astrocytes are active players of synaptic transmission. In the adult hippocampus, microglia are the other major glial cell-type. Microglia are highly dynamic and are closely associated with neurons and astrocytes. They react rapidly to modifications of their environment and are able to release molecules known to control neuronal function and synaptic transmission. Therefore, microglia display functional features of synaptic partners, but their involvement in the regulation of synaptic transmission has not yet been addressed.
We have used a combination of pharmacological approaches with electrophysiological analysis on acute hippocampal slices and ATP assays in purified cell cultures, to demonstrate that activation of microglia induces a rapid increase of spontaneous excitatory post-synaptic currents (EPSC). We found that this modulation is mediated by binding of ATP to P2Y1R located on astrocytes and is independent of TNFα or NOS2. Our data indicates that upon activation, microglia rapidly release small amount of ATP and astrocytes in turn amplified this release. Finally, P2Y1 stimulation of astrocytes increased EPSC frequency through an mGlur5-dependent mechanism.
These results reveal for the first time microglia as a genuine regulator of neurotransmission and place microglia as an upstream partner of astrocytes. Because pathological activation of microglia and alteration of neurotransmission are two early symptoms of most brain diseases, our work also provides a basis for understanding synaptic dysfunction in neuronal diseases.

Microglia (in green) are closely aposed to neurons (in gold). Pascual et al. have now shown that stimulation of microglia rapidly modulate AMPAergic synapses via astrocytes.

Proc Natl Acad Sci USA doi:10.1073/pnas.1111098109

Homeoprotein Phox2b commands a somatic-to-visceral switch in cranial sensory pathways.

Marie Embs — 2015-02-25T11:05:36Z

Taste and most sensory inputs required for the feedback regulation of digestive, respiratory and cardiovascular organs are conveyed to the central nervous system by so-called “visceral” sensory neurons located in three cranial ganglia (geniculate, petrosal and nodose), and integrated in the hindbrain by relay sensory neurons located in the nucleus of the solitary tract. Visceral sensory ganglia and the nucleus of the solitary tract all depend for their formation on the pan-visceral homeodomain transcription factor Phox2b, also required in efferent neurons to the viscera. We show here, by genetically tracing Phox2b+ cells, that in the absence of the protein many visceral sensory neurons (first- and second-order) survive. However, they adopt a fate —including molecular signature, cell positions and axonal projections— akin to that of somatic sensory neurons (first- and second-order), located in the trigeminal, superior and jugular ganglia and the trigeminal sensory nuclei, that convey touch and pain sensation from the oro-facial region. Thus, the cranial sensory pathways, somatic and visceral, are related, and Phox2b serves as a developmental switch from the former to the latter.

Proc Natl Acad Sci U S A. 2011 Dec 13 ;108(50):20018-23.