ENS - Départment de biologie

Pierre Paoletti, directeur de l'IBENS, élu membre de l'Académie des Sciences

Frédérique Godfroid — 2024-12-23T16:12:47Z

L'Académie des sciences se réjouit d'accueillir dès 2025, 18 nouveaux membres, scientifiques d'exception et figures de proue dans leurs disciplines respectives.
Ces nominations renforcent le rayonnement de l'Académie, qui continue à promouvoir l'excellence scientifique française et internationale

Communiqué de presse

CTNND2 moderates the pace of synaptic maturation and links human evolution to synaptic neoteny

Frédérique Godfroid — 2024-11-05T13:47:58Z

Authors
Nora Assendorp, Matteo Fossati, Baptiste Libé-Philippot, Eirini Christopoulou, Marine Depp, Roberta Rapone, Florent Dingli, Damarys Loew, Pierre Vanderhaeghen, Cécile Charrier.

Abstract

Human-specific genes are potential drivers of brain evolution. Among them, SRGAP2C has contributed to the emergence of features characterizing human cortical synapses, including their extended period of maturation. SRGAP2C inhibits its ancestral copy, the postsynaptic protein SRGAP2A, but the synaptic molecular pathways differentially regulated in humans by SRGAP2 proteins remain largely unknown. Here, we identify CTNND2, a protein implicated in severe intellectual disability (ID) in Cri-du-Chat syndrome, as a major partner of SRGAP2. We demonstrate that CTNND2 slows synaptic maturation and promotes neuronal integrity. During postnatal development, CTNND2 moderates neuronal excitation and excitability. In adults, it supports synapse maintenance. While CTNND2 deficiency is deleterious and results in synaptic loss of SYNGAP1, another major ID-associated protein, the human-specific protein SRGAP2C, enhances CTNND2 synaptic accumulation in human neurons. Our findings suggest that CTNND2 regulation by SRGAP2C contributes to synaptic neoteny in humans and link human-specific and ID genes at the synapse.

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Cell Rep. 2024 Oct 22 ;43(10):114797. doi : 10.1016/j.celrep.2024.114797

Single-molecule reconstruction of eukaryotic factor-dependent transcription termination

Frédérique Godfroid — 2024-09-09T13:20:40Z

Abstract

Factor-dependent termination uses molecular motors to remodel transcription machineries, but the associated mechanisms, especially in eukaryotes, are poorly understood. Here we use single-molecule fluorescence assays to characterize in real time the composition and the catalytic states of Saccharomyces cerevisiae transcription termination complexes remodeled by Sen1 helicase. We confirm that Sen1 takes the RNA transcript as its substrate and translocates along it by hydrolyzing multiple ATPs to form an intermediate with a stalled RNA polymerase II (Pol II) transcription elongation complex (TEC). We show that this intermediate dissociates upon hydrolysis of a single ATP leading to dissociation of Sen1 and RNA, after which Sen1 remains bound to the RNA. We find that Pol II ends up in a variety of states : dissociating from the DNA substrate, which is facilitated by transcription bubble rewinding, being retained to the DNA substrate, or diffusing along the DNA substrate. Our results provide a complete quantitative framework for understanding the mechanism of Sen1-dependent transcription termination in eukaryotes.

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Nat Commun. 2024 Jun 15 ;15(1):5113. doi : 10.1038/s41467-024-49527-z

Cécile Charrier, lauréate de la "Chaire d'excellence en biologie / santé" de France 2030

Frédérique Godfroid — 2024-06-28T07:10:32Z

Projet scientifique

synMODORG “Human-specific modifiers and activitydependent organizers of cortical circuit development and plasticity” / « Modificateurs spécifiques à l'homme et organisateurs dépendants de l'activité du développement et de la plasticité des circuits corticaux »

Le néocortex est la zone du cerveau la plus récente du point de vue de l'évolution et le siège des capacités cognitives supérieures qui caractérisent notre espèce, notamment la pensée abstraite, le langage symbolique et la flexibilité intellectuelle et sociale. Au cours de l'évolution humaine, les neurones corticaux se sont spécialisés pour mûrir sur de longues périodes, augmenter leur connectivité et acquérir des propriétés fonctionnelles spécifiques qui renforcent l'importance des interactions avec le monde extérieur et permettent d'intégrer beaucoup plus d'informations que dans d'autres espèces. Le projet synMODORG ambitionne de comprendre les mécanismes sous-jacents au niveau cellulaire et moléculaire et de déterminer les liens entre la spécialisation des neurones corticaux humains et la pathophysiologie des troubles neurodéveloppementaux tels que l'autisme et la déficience intellectuelle. Ces recherches seront essentielles pour mieux comprendre le cerveau humain et ouvrions de nouvelles perspectives pour le développement de traitements contre les troubles neurologiques.

Cet appel, opéré par l'ANR, permet de financer une équipe de recherche en France sur une durée de cinq ans. Ce dispositif vise à conserver et attirer en France les meilleurs chercheurs de leur discipline et ainsi renforcer l'excellence de la recherche française.
Confirmant l'ambition fixée avec le lancement du Plan Innovation santé 2030, volet santé de France 2030, de faire de la France un pays leader en santé, le Président de la République a annoncé en juin 2023 le lancement de ses différents dispositifs de soutien dans le champ de la recherche biomédicale afin de disposer d'une recherche d'excellence dans le champ de la Biologie/Santé.
Coordonnés en interministériel par l'Agence de l'innovation en santé, les bio-clusters, instituts hospitalo-universitaires, chaires d'excellence ont en commun de prendre en compte le besoin d'investissement sur l'ensemble de la chaîne de valeur : de la recherche fondamentale en sciences de la vie à la recherche translationnelle et clinique en santé et le soutien à l'innovation.

Dossier Presse lauréats Chaires Biologie-Santé

Imbalanced speciation pulses sustain the radiation of mammals

Frédérique Godfroid — 2024-06-10T15:33:42Z

Abstract

The evolutionary histories of major clades, including mammals, often comprise changes in their diversification dynamics, but how these changes occur remains debated. We combined comprehensive phylogenetic and fossil information in a new "birth-death diffusion" model that provides a detailed characterization of variation in diversification rates in mammals. We found an early rising and sustained diversification scenario, wherein speciation rates increased before and during the Cretaceous-Paleogene (K-Pg) boundary. The K-Pg mass extinction event filtered out more slowly speciating lineages and was followed by a subsequent slowing in speciation rates rather than rebounds. These dynamics arose from an imbalanced speciation process, with separate lineages giving rise to many, less speciation-prone descendants. Diversity seems to have been brought about by these isolated, fast-speciating lineages, rather than by a few punctuated innovations.

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Science. 2024 May 31 ;384(6699):1007-1012. doi : 10.1126/science.adj2793

Exon-junction complex association with stalled ribosomes and slow translation- independent disassembly

Frédérique Godfroid — 2024-06-04T08:15:52Z

Abstract

Exon junction complexes are deposited at exon-exon junctions during splicing. They are primarily known to activate non-sense mediated degradation of transcripts harbouring premature stop codons before the last intron. According to a popular model, exon-junction complexes accompany mRNAs to the cytoplasm where the first translating ribosome pushes them out. However, they are also removed by uncharacterized, translation-independent mechanisms. Little is known about kinetic and transcript specificity of these processes. Here we tag core subunits of exon-junction complexes with complementary split nanoluciferase fragments to obtain sensitive and quantitative assays for complex formation. Unexpectedly, exon-junction complexes form large stable mRNPs containing stalled ribosomes. Complex assembly and disassembly rates are determined after an arrest in transcription and/or translation. 85% of newly deposited exon-junction complexes are disassembled by a translation-dependent mechanism. However as this process is much faster than the translation-independent one, only 30% of the exon-junction complexes present in cells at steady state require translation for disassembly. Deep RNA sequencing shows a bias of exon-junction complex bound transcripts towards microtubule and centrosome coding ones and demonstrate that the lifetimes of exon-junction complexes are transcript-specific. This study provides a dynamic vision of exon-junction complexes and uncovers their unexpected stable association with ribosomes.

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Nat Commun. 2024 May 17 ;15(1):4209. doi : 10.1038/s41467-024-48371-5.

The pelvic organs receive no parasympathetic innervation

Frédérique Godfroid — 2024-06-03T13:05:37Z

Abstract

The pelvic organs (bladder, rectum, and sex organs) have been represented for a century as receiving autonomic innervation from two pathways - lumbar sympathetic and sacral parasympathetic - by way of a shared relay, the pelvic ganglion, conceived as an assemblage of sympathetic and parasympathetic neurons. Using single-cell RNA sequencing, we find that the mouse pelvic ganglion is made of four classes of neurons, distinct from both sympathetic and parasympathetic ones, albeit with a kinship to the former, but not the latter, through a complex genetic signature. We also show that spinal lumbar preganglionic neurons synapse in the pelvic ganglion onto equal numbers of noradrenergic and cholinergic cells, both of which therefore serve as sympathetic relays. Thus, the pelvic viscera receive no innervation from parasympathetic or typical sympathetic neurons, but instead from a divergent tail end of the sympathetic chains, in charge of its idiosyncratic functions.

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Elife. 2024 Mar 15:12:RP91576. doi : 10.7554/eLife.91576

Microglial TNFα controls daily changes in synaptic GABAARs and sleep slow waves

Frédérique Godfroid — 2024-05-03T14:57:36Z

Abstract

Microglia sense the changes in their environment. How microglia actively translate these changes into suitable cues to adapt brain physiology is unknown. We reveal an activity-dependent regulation of cortical inhibitory synapses by microglia, driven by purinergic signaling acting on P2RX7 and mediated by microglia-derived TNFα. We demonstrate that sleep induces microglia-dependent synaptic enrichment of GABA_ARs in a manner dependent on microglial TNFα and P2RX7. We further show that microglia-specific depletion of TNFα alters slow waves during NREM sleep and blunt memory consolidation in sleep-dependent learning tasks. Together, our results reveal that microglia orchestrate sleep-intrinsic plasticity of synaptic GABA_ARs, sculpt sleep slow waves, and support memory consolidation.

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J Cell Biol (2024) 223 (7) : e202401041. doi : 10.1083/jcb.202401041

Structural basis of DNA crossover capture by Escherichia coli DNA gyrase

Frédérique Godfroid — 2024-04-12T07:31:16Z

Abstract

DNA supercoiling must be precisely regulated by topoisomerases to prevent DNA entanglement. The interaction of type IIA DNA topoisomerases with two DNA molecules, enabling the transport of one duplex through the transient double-stranded break of the other, remains elusive owing to structures derived solely from single linear duplex DNAs lacking topological constraints. Using cryo–electron microscopy, we solved the structure of Escherichia coli DNA gyrase bound to a negatively supercoiled minicircle DNA. We show how DNA gyrase captures a DNA crossover, revealing both conserved molecular grooves that accommodate the DNA helices. Together with molecular tweezer experiments, the structure shows that the DNA crossover is of positive chirality, reconciling the binding step of gyrase-mediated DNA relaxation and supercoiling in a single structure.

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Science, 2024, April 12. Vol 384, Issue 6692. doi : 10.1126/science.adl5899

Shifted PAMs generate DNA overhangs and enhance SpCas9 post-catalytic complex dissociation

Frédérique Godfroid — 2024-04-05T12:34:29Z

Abstract

Using Sanger sequencing and high-throughput genome sequencing of DNA cleavage reactions, we find that the Streptococcus pyogenes SpCas9 complex responds to internal mechanical strain by robustly generating a distribution of overhanging, rather than blunt, DNA ends. Internal mechanical strain is generated by shifting (increasing or decreasing) the spacing between the RNA-DNA hybrid and the downstream canonical PAM. Up to 2-base 3' overhangs can be robustly generated via a 2-base increase in the distance between hybrid and PAM. We also use single-molecule experiments to reconstruct the full course of the CRISPR-SpCas9 reaction in real-time, structurally and kinetically monitoring and quantifying R-loop formation, the first and second DNA-incision events, and dissociation of the post-catalytic complex. Complex dissociation and release of broken DNA ends is a rate-limiting step of the reaction, and shifted SpCas9 is sufficiently destabilized so as to rapidly dissociate after formation of broken DNA ends.

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Nat Struct Mol Biol. 2023 Nov ;30(11):1707-1718. doi : 10.1038/s41594-023-01104-6.