Hommage à Arsène Bonafous-Murat (1935-2011)

Né à Paris le 21 mars 1935, Arsène Bonafous-Murat y est décédé le 18 avril 2011. Tout le monde s’accordera pour dire d’Arsène Bonafous-Murat à la fois qu’il était un de nos grands marchands d’estampes et qu’il avait un caractère affirmé. Arsène était le fils d’un chanteur d’opéra, Félix Bonafous-Murat, devenu marchand de timbres, qu’il n’a pas connu. Il fut momentanément élevé par sa tante Suzanne. De 1939 à 1942, il vécut dans une ferme, dans l’Yonne, époque dont il gardait de bons souvenirs..

Régulation de l'activité de Krox20 au cours de la mise en place du système nerveux central et périphérique

During embryonic development, the posterior part of vertebrates brain, or hindbrain, goes through a transient segmentation process along the anterio-posterior axis, leading to the definition of metameric units called rhombomeres. They correspond to neuronal differenciation units and allow the organization of cranial nerves. They also play a major role in cranio-facial structures development through regionalized production of neural crest. The Krox20 gene encodes a transcription factor which is expressed in rhombomeres r3 and r5. It has been shown that its expression in these domains is necessary to define and maintain them, as well as to generate the corresponding cranial nerves properly. Krox20 controls indeed the transcriptional expression of various genes implicated in particular in rhombomeres identity and intactness. Some cofactors of Krox20, as Nab or HCF-1, had been previously described but their role in vivo had not been addressed, in particular during hindbrain development. The first aim of my PhD was to better understand the mechanisms on which Krox20 activity relies in vivo and in particular the regulating roles of some of its cofactors. To address these questions, I performed a structure-function study in vivo using chick embryo as a model. I showed that Krox20 activity during hindbrain development relies on different domains of the protein depending on the transcriptional target considered. I also showed that Nab proteins are implicated in a negative feedback loop regulating Krox20 activation function, whereas HCF-1 is a positive cofactor of Krox20 for the activation of two of its transcriptional targets. Furthermore, this study allowed us to characterize new interaction sites between HCF-1 and Krox20. Krox20 is also a key factor of the myelination process in the peripheral nervous system (PNS), on which the rapid saltatory conduction along nerves relies. Various human pathologies are due to hypomyelination or demyelinating events. A Krox20 knock-out mouse model previously generated in the laboratory had shown a lack of myelination of the PNS in the absence of Krox20. This was due to a defect of differenciation of the myelinating Schwann cells in which Krox20 is normally expressed. Following this study, various mutations in Krox20 had been characterized in hereditary myelinopathies of the PNS, such as Charcot-Marie-Tooth diseases (CMT). In particular, one of these mutations, that leads to a severe early-onset subtype of recessive CMT, appears to abolish the interaction between Krox20 and its cofactors Nab. The second aim of my PhD was to characterize the role of Nab interaction with Krox20 during the myelination process and the hindbrain segmentation in vivo. For this purpose, I generated a mouse model of CMT carrying the mutation abolishing Krox20/Nab interaction. Homozygous mutant mice show a phenotype similar to what is observed in human patients. These mice have locomotion defects evolving progressively to limbs paralysis and are affected by a severe defect in PNS myelination. My studies showed that the myelination process is first delayed, leading subsequently to an hypomyelination of the PNS, followed by demyelination. These defects appear to be linked to a delay in proliferation arrest of Schwann cells and a disregulation of gene expression in these cells. Surprisingly, Nab proteins appear to be positive cofactors of Krox20 in Schwann cells. Furthermore, I showed that these mutant mice present cranial nerves abnormalities which are compatible with functional impairments observed in human patients carrying this mutation. In summary, the studies made during my PhD allowed to show the complexity of Krox20 transcriptional activity, relying on different target-specific domains of the protein, as well as to better characterize the role of two of its cofactors during hindbrain development. This work also lead to the generation of a mouse model for a severe form of CMT, allowing a better understanding of its complex pathomechanisms.Au cours de ma thèse, j'ai étudié le rôle in vivo du facteur de transcription Krox20 durant le développement précoce du cerveau postérieur des vertébrés et durant le processus de myélinisation du système nerveux périphérique. Je me suis plus particulièrement intéressée aux mécanismes impliqués dans la régulation de son activité via son interaction avec divers co-facteurs. Lors du développement embryonnaire, le cerveau postérieur des vertébrés, ou rhombencéphale, présente une segmentation transitoire le long de l'axe antéro-postérieur, aboutissant à la formation d'unités de différenciation neuronales. Le gène maître Krox20, codant un facteur de transcription à doigts de zinc, est exprimé précocement dans le rhombencéphale et est nécessaire à son développement, ainsi qu'à l'organisation correcte des nerfs crâniens. Une étude structure-fonction de Krox20 réalisée in vivo m'a permis de montrer que son activité au niveau du rhombencéphale implique différents domaines de la protéine en fonction des cibles transcriptionnelles considérées. J'ai de plus étudié plus spécifiquement le rôle de ses co-facteurs Nab et Hcf-1, montrant qu'ils jouent respectivement un rôle répresseur et activateur de l'activité de Krox20 lors du développement du rhombencéphale. Krox20 est également un gène-clé du processus de myélinisation du système nerveux périphérique et diverses mutations l'affectant ont été caractérisées chez des patients atteints de neuropathies démyélinisantes héréditaires, nommées maladies de Charcot-Marie-Tooth. J'ai généré une lignée de souris portant l'une de ces mutations, abolissant l'interaction entre Krox20 et les Nab. Ce modèle murin, présentant des défauts similaires à ceux observés chez les patients humains, m'a permis de confirmer le rôle majeur de l'interaction entre Krox20 et les Nab dans le processus de myélinisation. J'ai par ailleurs pu montrer que l'hypomyélinisation observée reposait sur un phénotype complexe, lié à un retard du processus de myélinisation suivi d'une dégradation de la myéline formée. Ceci suggère un rôle majeur de Krox20 et des Nab durant différentes étapes séquentielles de la myélinisation du système nerveux périphérique

Myelin Plasticity and Repair: Neuro-Glial Choir Sets the Tuning

International audienceThe plasticity of the central nervous system (CNS) in response to neuronal activity has been suggested as early as 1894 by Cajal (1894). CNS plasticity has first been studied with a focus on neuronal structures. However, in the last decade, myelin plasticity has been unraveled as an adaptive mechanism of importance, in addition to the previously described processes of myelin repair. Indeed, it is now clear that myelin remodeling occurs along with life and adapts to the activity of neuronal networks. Until now, it has been considered as a two-part dialog between the neuron and the oligodendroglial lineage. However, other glial cell types might be at play in myelin plasticity. In the present review, we first summarize the key structural parameters for myelination, we then describe how neuronal activity modulates myelination and finally discuss how other glial cells could participate in myelinic adaptivity

Interaction between Neurons and the Oligodendroglial Lineage in Multiple Sclerosis and Its Preclinical Models

International audienceMultiple sclerosis (MS) is a complex central nervous system inflammatory disease leading to demyelination and associated functional deficits. Though endogenous remyelination exists, it is only partial and, with time, patients can enter a progressive phase of the disease, with neurodegeneration as a hallmark. Though major therapeutic advances have been made, with immunotherapies reducing relapse rate during the inflammatory phase of MS, there is presently no therapy available which significantly impacts disease progression. Remyelination has been shown to favor neuroprotection, and it is thus of major importance to better understand remyelination mechanisms in order to promote them and hence preserve neurons. A crucial point is how this process is regulated through the neuronal crosstalk with the oligodendroglial lineage. In this review, we present the current knowledge on neuron interaction with the oligodendroglial lineage, in physiological context as well as in MS and its experimental models. We further discuss the therapeutic possibilities resulting from this research field, which might allow to support remyelination and neuroprotection and thus limit MS progression

Identification of synthetic dyes in early colour photographs using capillary electrophoresis and electrospray ionisation-mass spectrometry

International audienceCapillary electrophoresis with photodiode array detection (CE-PDA) and with electrospray ionisation-mass spectrometry (CE-ESI-MS) was used for the separation and the identification of 23 synthetic organic dyes, among those used in early 20th century colour photographs such as autochromes. Both cationic and anionic dyes could be separated within 15 min using a single CE-PDA method. The method was used as the basis to develop a CE-ESI-MS methodology through the optimisation of the relevant ESI and MS parameters. Sheath liquid composition, nebulising gas pressure, drying gas flow rate and drying gas temperature were found to influence the sensitivity of the detection. These parameters were optimised in positive and negative ion modes for cationic dyes and anionic dyes, respectively. The two analyses could be carried out successively on a single sample. In view of the application to cultural heritage objects, the CE-ESI-MS analytical procedure was applied to identify the dyes in a Filmcolor artefact, late version of the autochrome. The results complemented and enhanced current knowledge as four cationic dyes and three anionic dyes were identified. Four additional dyes are proposed as possibly present as traces

Disruption of Krox20-Nab interaction in the mouse leads to peripheral neuropathy with biphasic evolution.

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Mechanisms of sodium channel clustering and its influence on axonal impulse conduction

International audienceThe efficient propagation of action potentials along nervous fibers is necessary for animals to interact with the environment with timeliness and precision. Myelination of axons is an essential step to ensure fast action potential propagation by saltatory conduction, a process that requires highly concentrated voltage-gated sodium channels at the nodes of Ranvier. Recent studies suggest that the clustering of sodium channels can influence axonal impulse conduction in both myelinated and unmyelinated fibers, which could have major implications in disease, particularly demyelinating pathology. This comprehensive review summarizes the mechanisms governing the clustering of sodium channels at the peripheral and central nervous system nodes and the specific roles of their clustering in influencing action potential conduction. We further highlight the classical biophysical parameters implicated in conduction timing, followed by a detailed discussion on how sodium channel clustering along unmyelinated axons can impact axonal impulse conduction in both physiological and pathological contexts. Keywords Voltage-gated sodium channel Á Node of ranvier Á Axon–glial interactions Á Myelin Á Action potential propagation Á Neurological disease Abbreviations AP Action potential AIS Axon initial segment Na v Voltage-gated sodium channels K v Voltage-gated potassium channels PNS Peripheral nervous system CNS Central nervous system CAM Cell-adhesion molecule ECM Extracellular matrix Nfasc Neurofascin GPI Glycosyl phosphatidylinositol MS Multiple sclerosis GBS Guillain–Barré syndrome EAE Experimental autoimmune encephalomyeliti

Soigner l'esprit

Les affects qui débordent les corps, les souffrances de l’esprit, les règles morales qui s’attachent à la sexualité comme à la famille, mettent en relation les disciplines expertes du psychisme avec les traditions religieuses. Les premières ont certes pris l’ascendant aujourd’hui sur les secondes, mais la prise en charge séculière de la cure des âmes est complexe et diverse, sans doute plus que celle du soin des corps depuis longtemps déléguée sans reste à la médecine. Les contributions rassemblées dans ce dossier thématique portent sur des espaces de psychothérapies et de religions aussi divers que ceux de l’Angleterre, de la Grèce, de la France, du Québec ou du Portugal. Où se croisent les patients de divers horizons sociaux au sein desquels la variable de genre n’est jamais neutre. Où se confrontent et dialoguent les professionnels de diverses disciplines déployées sur l’arc « psy » allant de la théorie à la clinique, mais aussi les confesseurs et thérapeutes de multiples obédiences. Dans la rubrique varia, on trouvera en outre trois articles qui traitent de sujets bien différents : le premier nous fait remonter dans l’imaginaire colonial du pèlerinage à La Mecque, singulièrement hanté par la menace de choléra ; le second nous transporte sur l’île Maurice avec son peuplement indien qui s’interroge encore sur son marquage par la structure de castes ; le troisième enfin nous ramène vers les processus contrastés d’adhésion religieuse dans une langue et une éducation aussi sécularisées que celles de la France contemporaine