The dystroglycan: Nestled in an adhesome during embryonic development

AbstractInvertebrate and vertebrate development relies on complex processes that require many coordinated cell functions including cell adhesion, migration, proliferation and polarization. These processes depend on tissues and are spatio-temporally regulated by specific interactions between cells and between cells and the extracellular matrices. The dystroglycan, a transmembrane receptor that binds multiple extracellular matrix proteins, is expressed from oogenesis to organogenesis. There are increasing data suggesting that the axis, consisting of extracellular component–dystroglycan–cytoplasmic proteins, controls both the adhesion of cells to matrices as well as the transduction of signals coming from or directed to matrices. In this article, we review current advances leading to consider that the dystroglycan is a key protein nestled in an adhesome involved in mechanisms of cell adhesion during embryonic development

The translational repressor 4E-BP mediates hypoxia-induced defects in myotome cells.

International audienceCell growth, proliferation, differentiation and survival are influenced by the availability of oxygen. The effect of hypoxia on embryonic cells and the underlying molecular mechanisms to maintain cellular viability are still poorly understood. In this study, we show that hypoxia during Xenopus embryogenesis rapidly leads to a significant developmental delay and to cell apoptosis after prolonged exposure. We provide strong evidence that hypoxia does not affect somitogenesis but affects the number of mitotic cells and muscle-specific protein accumulation in somites, without interfering with the expression of MyoD and MRF4 transcription factors. We also demonstrate that hypoxia reversibly decreases Akt phosphorylation and increases the total amount of the translational repressor 4E-BP, in combination with an increase of the 4E-BP associated with eIF4E. Interestingly, the inhibition of PI3-kinase or mTOR, with LY29002 or rapamycin, respectively, triggers the 4E-BP accumulation in Xenopus embryos. Finally, the overexpression of the non-phosphorylatable 4E-BP protein induces, similar to hypoxia, a decrease in mitotic cells and a decrease in muscle-specific protein accumulation in somites. Taken together, our studies suggest that 4E-BP plays a central role under hypoxia in promoting the cap-independent translation at the expense of cap-dependent translation and triggers specific defects in muscle development

Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies.

peer reviewedNemaline myopathy (NM) is a muscle disorder with broad clinical and genetic heterogeneity. The clinical presentation of affected individuals ranges from severe perinatal muscle weakness to milder childhood-onset forms, and the disease course and prognosis depends on the gene and mutation type. To date, 14 causative genes have been identified, and ACTA1 accounts for more than half of the severe NM cases. ACTA1 encodes α-actin, one of the principal components of the contractile units in skeletal muscle. We established a homogenous cohort of ten unreported families with severe NM, and we provide clinical, genetic, histological, and ultrastructural data. The patients manifested antenatal or neonatal muscle weakness requiring permanent respiratory assistance, and most deceased within the first months of life. DNA sequencing identified known or novel ACTA1 mutations in all. Morphological analyses of the muscle biopsy specimens showed characteristic features of NM histopathology including cytoplasmic and intranuclear rods, cytoplasmic bodies, and major myofibrillar disorganization. We also detected structural anomalies of the perinuclear space, emphasizing a physiological contribution of skeletal muscle α-actin to nuclear shape. In-depth investigations of the nuclei confirmed an abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, forming the main constituents of the nuclear lamina and the LINC complex and ensuring nuclear envelope integrity. To validate the relevance of our findings, we examined muscle samples from three previously reported ACTA1 cases, and we identified the same set of structural aberrations. Moreover, we measured an increased expression of cardiac α-actin in the muscle samples from the patients with longer lifespan, indicating a potential compensatory effect. Overall, this study expands the genetic and morphological spectrum of severe ACTA1-related nemaline myopathy, improves molecular diagnosis, highlights the enlargement of the perinuclear space as an ultrastructural hallmark, and indicates a potential genotype/phenotype correlation

Leveraging Natural History Data in One- and Two-Arm Hierarchical Bayesian Studies of Rare Disease Progression

peer reviewedThe small sample sizes inherent in rare and pediatric disease settings offer significant challenges for clinical trial design. In such settings, Bayesian adaptive trial methods can often pay dividends, allowing the sensible incorporation of auxiliary data and other relevant information to bolster that collected by the trial itself. Previous work has also included the use of one-arm trials augmented by the participants’ own natural history data, from which the future course of the disease in the absence of intervention can be predicted. Patient response can then be defined by the degree to which post-intervention observations are inconsistent with the predicted “natural” trajectory. While such trials offer obvious advantages in efficiency and ethical hazard (since they expose no new patients to a placebo, anathema to patients or their parents and caregivers), they can offer no protection against bias arising from the presence of any “placebo effect,” the tendency of patients to improve merely by being in the trial. In this paper, we investigate the impact of both static and transient placebo effects on one-arm responder studies of this type, as well as two-arm versions that incorporate a small concurrent placebo group but still borrow strength from the natural history data. We also propose more traditional Bayesian changepoint models that specify a parametric functional form for the patient’s post-intervention trajectory, which in turn allow quantification of the treatment benefit in terms of the model parameters, rather than semi-parametrically in terms of a response relative to some “null” model. We compare the operating characteristics of our designs in the context of an ongoing investigation of centronuclear myopathies (CNMs), a group of congenital neuromuscular diseases whose most common and severe form is X-linked, affecting approximately 1 in 50,000 newborn boys. Our results indicate our two-arm responder and changepoint methods can offer protection against placebo effects, improving power while protecting the trial’s Type I error rate. However, further research into innovative trial designs as well as ongoing dialog with regulatory authorities remain critically important in rare disease research

Étude des mécanismes moléculaires de l'adressage de deux nucléotide-pyrophosphatases/phosphodiestérases dans les cellules épithéliales polarisées

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Danses classiques indiennes

Cette vidéo présente les danses traditionnelles du sud de l’Inde et plus précisement du Tamil Nadu (தமிழ் நாடு). Notamment du Bharata natyam, des danses folkloriques et du théâtre dansé. Ces pratiques vous sont présentées par Chantal Vadrot, présidente de l’association Anjali Mudra. Les images proviennent des répétitions et spectacles créés par l’association

Expression polarisée des phosphodiestérases de type I dans les cellules épithéliales

Les phosphodiestérases de type I sont exprimées différemment selon le type cellulaire. Trois membres ont été identifiés, PC-1, B10 et l’autotaxine. Elles ont entre 40 et 50 % d’identité dans leur séquence en acides aminés. Les hépatocytes expriment à la fois B10 et PC-1 sur leur membrane plasmique. Cependant, B10 est exclusivement localisée au pôle apical tandis que PC-1 est localisée au pôle basolatéral. Au cours de sa biosynthèse dans les hépatocytes, B10 passe transitoirement par le pôle basolatéral avant d’atteindre le pôle apical. L’étape de transcytose entre le pôle basolatéral et le pôle apical fait intervenir un sous-compartiment tubulaire de l’endosome identique à celui du récepteur des IgA polymériques. Transfectées dans les cellules MDCK d’origine rénale et Caco-2 d’origine intestinale, B10 et PC-1 sont exprimées respectivement au pôle apical et basolatéral, comme dans les hépatocytes. Cependant le transport de B10 a lieu directement vers la surface apicale dans les cellules MDCK; il a lieu en partie directement et en partie par transcytose dans les cellules Caco-2. La troncation du domaine cytoplasmique de PC-1 produit une protéine apicale, ce qui indique que le domaine cytoplasmique porte le signal d’adressage de PC-1 vers la membrane plasmique basolatérale. La recherche du signal d’adressage apical de B10 est en cours

An adhesome comprising laminin, dystroglycan and myosin IIA is required during notochord development in Xenopus laevis.

International audienc

Molecular screening of xerophilic Aspergillus strains producing mycophenolic acid

International audienc