Altered splicing of Tau in DM1 is different from the foetal splicing process

AbstractAmong the different mechanisms underlying the etiopathogenesis of myotonic dystrophy type 1 (DM1), a backward reprogramming to a foetal splicing machinery is an interesting hypothesis. To address this possibility, Tau splicing, which is regulated during development and modified in DM1, was analyzed. Indeed, a preferential expression of the foetal Tau isoform, instead of the six normally found, is observed in adult DM1 brains. By using two cell lines, we show here that the cis-regulating elements necessary to generate the unique foetal Tau isoform are dispensable to reproduce the trans-dominant effect induced by DM1 mutation on Tau exon 2 inclusion. Our results suggest that the mis-splicing of Tau in DM1 is resulting from a disease-associated mechanism

A functional network of highly pure enteric neurons in a dish

The enteric nervous system (ENS) is the intrinsic nervous system that innervates the entire digestive tract and regulates major digestive functions. Recent evidence has shown that functions of the ENS critically rely on enteric neuronal connectivity; however, experimental models to decipher the underlying mechanisms are limited. Compared to the central nervous system, for which pure neuronal cultures have been developed for decades and are recognized as a reference in the field of neuroscience, an equivalent model for enteric neurons is lacking. In this study, we developed a novel model of highly pure rat embryonic enteric neurons with dense and functional synaptic networks. The methodology is simple and relatively fast. We characterized enteric neurons using immunohistochemical, morphological, and electrophysiological approaches. In particular, we demonstrated the applicability of this culture model to multi-electrode array technology as a new approach for monitoring enteric neuronal network activity. This in vitro model of highly pure enteric neurons represents a valuable new tool for better understanding the mechanisms involved in the establishment and maintenance of enteric neuron synaptic connectivity and functional networks

Le développement neuronal (rôle de la protéine adaptatrice CD3zeta et mécanismes régulant la fonction du récepteur de chimiokine CXCR4)

Le développement neuronal est assuré par un ensemble de mécanismes complexes permettant à terme la formation d'un réseau fonctionnel. Des données récentes montrent que des molécules bien décrites dans le système immunitaire ont également un rôle non immun dans des étapes fondamentales du développement cérébral. C'est dans ce contexte que nous avons étudié la molécule adaptatrice CD3zeta et le récepteur de chimiokine CXCR4. A des stades précoces de développement de neurones en culture, nous avons montré que CD3zeta est sélectivement associé aux cônes de croissance et aux filopodes. Des approches combinées de perte et de gain de fonction ont montré un rôle inhibiteur de CD3zeta dans la régulation du développement dendritique. Nos résultats suggèrent une nouvelle fonction de CD3zeta dans le contrôle de la morphogénèse dendritique. La chimiokine SDF-1 et son récepteur CXCR4 ont un rôle crucial dans plusieurs aspects du développement neuronal. Au cours de la formation des prolongements neuronaux, il a été montré que SDF-1 régule spécifiquement la formation de l axone sans affecter les autres neurites. Nous avons montré que la stimulation du récepteur CXCR4 par son ligand SDF-1 induit l internalisation du récepteur dans les dendrites mais pas dans l axone. Ce résultat suggère que l absence d internalisation de CXCR4 dans le domaine axonal pourrait être un mécanisme permettant une action sélective de SDF-1 sur la pousse axonale. Nos résultats révèlent un rôle inédit de CD3zeta dans le développement neuronal et un mécanisme de régulation original de CXCR4 pouvant favoriser l action sélective de SDF-1 sur les axones.Neuronal development is achieved by a complex set of mechanisms leading ultimately to the formation of a functional network. Recent data show that well-known molecules of the immune system also have non immune functions in critical stages of cerebral development. In this context, we studied the adaptor molecule CD3zeta and the chemokine receptor CXCR4. At early stages of neuronal development in culture, we have shown that CD3zeta is selectively associated with growth cones and filopodia. A combination of loss- and gain-of-function experiments in cultured neurons showed an inhibitory function of CD3zeta in dendrite development. These findings reveal a novel role of CD3zeta in the control of dendrite morphogenesis. The chemokine SDF-1 and its receptor CXCR4 have a critical role in many aspects of neuronal development. During the formation of neuronal processes, it has been shown that SDF-1 selectively regulates axonal patterning and does not affect the other neurites. We found that the stimulation of CXCR4 by SDF-1 induces receptor internalization in the somatodendritic domain but not in axons. This result suggests that the lack of CXCR4 internalization in axons might be a mechanism used to allow a selective action of SDF-1 in axonal growth. Our results reveal a novel role of CD3zeta in neuronal development and an original regulatory mechanism for CXCR4 that could promote a selective action of SDF-1 on axons.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Dendrite-selective redistribution of the chemokine receptor CXCR4 following agonist stimulation

The chemokine SDF-1 is a secreted protein that plays a critical role in several aspects of neuron development through interaction with its unique receptor CXCR4. A key mechanism that controls neuron responsiveness to extracellular signals during neuronal growth is receptor endocytosis. Since we previously reported that SDF-1 regulates axon development without affecting the other neurites, we asked whether this could correlate with a compartment-selective trafficking of CXCR4. We thus studied CXCR4 behavior upon SDF-1 exposure in rat hippocampus slices and in transfected neuron cultures. A massive agonist-induced redistribution of CXCR4 in endosomes was observed in dendrites whereas no modification was evidenced in axons. Our data suggest that CXCR4 trafficking may play a role in mediating selective effects of SDF-1 on distinct neuronal membrane subdomains

Gestational Hypothyroxinemia Affects Glutamatergic Synaptic Protein Distribution and Neuronal Plasticity Through Neuron-Astrocyte Interplay

International audienceGestational hypothyroxinemia, characterized by low levels of maternal thyroxine (T4) during gestation, is closely associated with cognitive impairment in offspring. Studies in animal models have shown that this condition alters neuronal glutamatergic synapses in the hippocampus. Given that astrocytes critically contribute to the establishment and functioning of synapses, the aim of this study was to determine the effects of gestational hypothyroxinemia on the capacity of astrocytes to regulate glutamatergic synapses. In an in vitro co-culture model of astrocytes and hippocampal neurons, gestational hypothyroxinemia profoundly affected the synaptic patterns of GluN1 and CD3ζ in an astrocyte-dependent manner. These effects were associated with impaired plasticity that was dependent on both neuronal and astrocyte contributions. These results highlight the importance of neuron-astrocyte interplay in the deleterious effects of gestational hypothyroxinemia and the timely diagnosis and treatment of this condition during gestation to ensure proper central nervous system development in offspring

Semaphorin 3A controls enteric neuron connectivity and is inversely associated with synapsin 1 expression in Hirschsprung disease

International audienceMost of the gut functions are controlled by the enteric nervous system (ENS), a complex network of enteric neurons located throughout the wall of the gastrointestinal tract. The formation of ENS connectivity during the perinatal period critically underlies the establishment of gastrointestinal motility, but the factors involved in this maturation process remain poorly characterized. Here, we examined the role of Semaphorin 3A (Sema3A) on ENS maturation and its potential implication in Hirschsprung disease (HSCR), a developmental disorder of the ENS with impaired colonic motility. We found that Sema3A and its receptor Neuropilin 1 (NRP1) are expressed in the rat gut during the early postnatal period. At the cellular level, NRP1 is expressed by enteric neurons, where it is particularly enriched at growth areas of developing axons. Treatment of primary ENS cultures and gut explants with Sema3A restricts axon elongation and synapse formation. Comparison of the ganglionic colon of HSCR patients to the colon of patients with anorectal malformation shows reduced expression of the synaptic molecule synapsin 1 in HSCR, which is inversely correlated with Sema3A expression. Our study identifies Sema3A as a critical regulator of ENS connectivity and provides a link between altered ENS connectivity and HSCR

Is perinatal butyrate, through maternal supplementation, able to prevent cognitive impairment due to intrauterine growth restriction in a rat model ?

International audienc

Is perinatal butyrate, through maternal supplementation, able to prevent cognitive impairment due to intrauterine growth restriction in a rat model ?

International audienc

Is perinatal butyrate, through maternal supplementation, able to prevent cognitive impairment due to intrauterine growth restriction in a rat model ?

International audienc