Cyclin-dependent kinase 7 contributes to myelin maintenance in the adult central nervous system and promotes myelin gene expression.

Mechanisms regulating oligodendrocyte differentiation, developmental myelination and myelin maintenance in adulthood are complex and still not completely described. Their understanding is crucial for the development of new protective or therapeutic strategies in demyelinating pathologies such as multiple sclerosis. In this perspective, we have investigated the role of Cyclin-dependent kinase 7 (Cdk7), a kinase involved in cell-cycle progression and transcription regulation, in the oligodendroglial lineage. We generated a conditional knock-out mouse model in which Cdk7 is invalidated in post-mitotic oligodendrocytes. At the end of developmental myelination, the number and diameter of myelinated axons, as well as the myelin structure, thickness and protein composition, were normal. However, in young adult and in aged mice, there was a higher number of small caliber myelinated axons associated with a decreased mean axonal diameter, myelin sheaths of large caliber axons were thinner, and the level of some major myelin-associated proteins was reduced. These defects were accompanied by the appearance of an abnormal clasping phenotype. We also used an in vitro oligodendroglial model and showed that Cdk7 pharmacological inhibition led to an altered myelination-associated morphological modification combined with a decreased expression of myelin-specific genes. Altogether, we identified novel functions for Cdk7 in CNS myelination.

Efficacy of Sensory Interventions on School Participation of Children With Sensory Disorders: A Systematic Review.

Research demonstrates lower school participation in children with sensory disorders. However, the scientific body of evidence supporting existing sensory intervention modalities is difficult to tackle. More specifically, the literature appears poorly organized, with a highly variable terminology, often with nonoverlapping definitions and lack of good keywords classification that would help organize the diversity of approaches. This systematic review organizes the body of evidence for 3 specific approaches (sensory based, sensorimotor, and sensory integration) and questions their efficacy in improving school participation for children with sensory disorders. Two methods were compared: first, a standard systematic review of the literature in 3 databases using appropriate keywords and descriptors, then an original method based on forward and backward citation connections. A total of 28 studies were retrieved, of which only 7 used the standard method for systematic reviews. For sensory-based approaches, the efficacy of weighted-vest varies according to different factors such as the protocol of use. For sensorimotor approaches, the efficacy of therapy balls, air cushions, platform swing, and physical exercise varies according to the child's sensory characteristics. The efficacy of the sensory integration approach remains mixed across studies.

Molecular Mechanisms Involved in Schwann Cell Plasticity.

Schwann cell incredible plasticity is a hallmark of the utmost importance following nerve damage or in demyelinating neuropathies. After injury, Schwann cells undergo dedifferentiation before redifferentiating to promote nerve regeneration and complete functional recovery. This review updates and discusses the molecular mechanisms involved in the negative regulation of myelination as well as in the reprogramming of Schwann cells taking place early following nerve lesion to support repair. Significant advance has been made on signaling pathways and molecular components that regulate SC regenerative properties. These include for instance transcriptional regulators such as c-Jun or Notch, the MAPK and the Nrg1/ErbB2/3 pathways. This comprehensive overview ends with some therapeutical applications targeting factors that control Schwann cell plasticity and highlights the need to carefully modulate and balance this capacity to drive nerve repair.

Adult bone marrow mesenchymal and neural crest stem cells are chemoattractive and accelerate motor recovery in a mouse model of spinal cord injury.

INTRODUCTION: Stem cells from adult tissues were considered for a long time as promising tools for regenerative therapy of neurological diseases, including spinal cord injuries (SCI). Indeed, mesenchymal (MSCs) and neural crest stem cells (NCSCs) together constitute the bone marrow stromal stem cells (BMSCs) that were used as therapeutic options in various models of experimental SCI. However, as clinical approaches remained disappointing, we thought that reducing BMSC heterogeneity should be a potential way to improve treatment efficiency and reproducibility. METHODS: We investigated the impact of pure populations of MSCs and NCSCs isolated from adult bone marrow in a mouse model of spinal cord injury. We then analyzed the secretome of both MSCs and NCSCs, and its effect on macrophage migration in vitro. RESULTS: We first observed that both cell types induced motor recovery in mice, and modified the inflammatory reaction in the lesion site. We also demonstrated that NCSCs but especially MSCs were able to secrete chemokines and attract macrophages in vitro. Finally, it appears that MSC injection in the spinal cord enhance early inflammatory events in the blood and spinal cord of SCI mice. CONCLUSIONS: Altogether, our results suggest that both cell types have beneficial effects in experimental SCI, and that further investigation should be dedicated to the regulation of the inflammatory reaction following SCI, in the context of stem cell-based therapy but also in the early-phase clinical management of SCI patients.

Interactions of a DNA-bound transcriptional activator with the TBP-TFIIA-TFIIB-promoter quaternary complex.

Site-specific protein-DNA photo-cross-linking was used to show that, when bound to its cognate site at various distances upstream of the TATA element, the chimeric transcriptional activator GAL4-VP16 can physically interact with a TATA box-binding protein (TBP)- transcription factor IIA (TFIIA)-TFIIB complex assembled on the TATA element. This result implies DNA bending and looping of promoter DNA as a result of the physical interaction between GAL4-VP16 and an interface of the TBP-TFIIA-TFIIB complex. This protein-protein interaction on promoter DNA minimally requires the presence of one GAL4 binding site and the formation of a quaternary complex containing TBP, TFIIB, and TFIIA on the TATA element. Notably, the topology of the TBP-TFIIA-TFIIB-promoter complex is not altered significantly by the interaction with DNA-bound activators. We also show that the ability of GAL4-VP16 to activate transcription through a single GAL4 binding site varies according to its precise location and orientation relative to the TATA element and that it can approach the efficiency obtained with multiple binding sites. Taken together, our results indicate that the spatial positioning of the DNA-bound activation domain is important for efficient activation, possibly by maximizing its interactions with the transcriptional machinery including the TBP-TFIIA-TFIIB-promoter quaternary complex.

Characterization of human herpesvirus 6 variant B immediate-early 1 protein modifications by small ubiquitin-related modifiers.

The human herpesvirus 6 (HHV-6) immediate-early (IE) 1 protein undergoes SUMOylation events during the infectious process. In the present work, we report that Lys-802 (K-802) of IE1 from HHV-6 variant B is the only target residue capable of conjugation to SUMO-1/SMT3C/Sentrin-1, SUMO-2/SMT3A/Sentrin-3 or SUMO-3/SMT3B/Sentrin-2 as determined by transfection and in vitro SUMOylation experiments. PolySUMOylated forms of IE1 were also observed, suggesting that SUMO branching occurs at the K-802 residue. Overexpression of SUMO-1, -2 and -3 led to an overall increase in IE1 levels, irrespective of K-802. The SUMO residues could be efficiently removed by incubating SUMOylated IE1 with SENP1, a recently identified SUMO peptidase. SUMOylation-deficient mutants of IE1 co-localized with nuclear promyelocytic leukaemia protein (PML) oncogenic domains (PODs) as efficiently as WT IE1, indicating that POD targeting is independent of IE1 SUMOylation status. However, in contrast to infection, PODs did not aggregate in IE1B-transfected cells, suggesting that other viral proteins are involved in the process. Transactivation studies indicated that IE1, in combination with IE2, could efficiently transactivate diverse promoters, independent of its SUMOylation status. Overall, the results presented provide a detailed biochemical characterization of post-translational modifications of the HHV-6 IE1 protein by SUMO peptides, contributing to our understanding of the complex interactions between herpesviruses and the SUMO-conjugation pathway.