2-Benzyl-1,3-diphenyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine

In the title compound, C31H25NO, the oxazine ring adopts a half-chair conformation. The dihedral angles between the phenyl rings and the naphthyl ring system are 70.89 (8), 37.34 (10) and 9.42 (10)°. The crystal structure is stabilized by an aromatic π–π stacking inter­action, with a centroid–centroid distance of 3.879 (3) Å

Regulated Activation of the PAR Polarity Network Ensures a Timely and Specific Response to Spatial Cues

How do cells polarize at the correct time and in response to the correct cues? In the C. elegans zygote, the timing and geometry of polarization rely on a single dominant cue-the sperm centrosome-that matures at the end of meiosis and specifies the nascent posterior. Polarization requires that the conserved PAR proteins, which specify polarity in the zygote, be poised to respond to the centrosome. Yet, how and when PAR proteins achieve this unpolarized, but responsive, state is unknown. We show that oocyte maturation initiates a fertilization-independent PAR activation program. PAR proteins are initially not competent to polarize but gradually acquire this ability following oocyte maturation. Surprisingly, this program allows symmetry breaking even in unfertilized oocytes lacking centrosomes. Thus, if PAR proteins can respond to multiple polarizing cues, how is specificity for the centrosome achieved? Specificity is enforced by Polo-like and Aurora kinases (PLK-1 and AIR-1 in C. elegans), which impose a delay in the activation of the PAR network so that it coincides with maturation of the centrosome cue. This delay suppresses polarization by non-centrosomal cues, which can otherwise trigger premature polarization and multiple or reversed polarity domains. Taken together, these findings identify a regulatory program that enforces proper polarization by synchronizing PAR network activation with cell cycle progression, thereby ensuring that PAR proteins respond specifically to the correct cue. Temporal control of polarity network activity is likely to be a common strategy to ensure robust, dynamic, and specific polarization in response to developmentally deployed cues

aPKC Cycles between Functionally Distinct PAR Protein Assemblies to Drive Cell Polarity

The conserved polarity effector proteins PAR-3, PAR-6, CDC-42, and atypical protein kinase C (aPKC) form a core unit of the PAR protein network, which plays a central role in polarizing a broad range of animal cell types. To functionally polarize cells, these proteins must activate aPKC within a spatially defined membrane domain on one side of the cell in response to symmetry-breaking cues. Using the Caenorhabditis elegans zygote as a model, we find that the localization and activation of aPKC involve distinct, specialized aPKC-containing assemblies: a PAR-3-dependent assembly that responds to polarity cues and promotes efficient segregation of aPKC toward the anterior but holds aPKC in an inactive state, and a CDC-42-dependent assembly in which aPKC is active but poorly segregated. Cycling of aPKC between these distinct functional assemblies, which appears to depend on aPKC activity, effectively links cue-sensing and effector roles within the PAR network to ensure robust establishment of polarity.This work was supported by a Faculty Fellowship from Newcastle University and a Royal Society Research Grant (RG2015R2 to J. Rodriguez), a BBSRC PhD fellowship (J.M.), a PhD fellowship from Newcastle University (A.G.G.), Wellcome Trust Senior and Principal Research Fellowships (054523, to J.A.; 080007, to D.StJ.), a University of Cambridge Studentship via the Wellcome Trust PhD Program in Developmental Biology (A.R.F.), and the Francis Crick Institute (N.W.G.), which receives its core funding from Cancer Research UK (FC001086), the UK Medical Research Council (FC001086), and the Wellcome Trust (FC001086). N.W.G. and J. Rodriguez are members of the GENiE network supported by COST Action BM1408 and EMBO

Note di Patologia Vegetale

Volume: 3Start Page: 1End Page: 3

Mécanismes moléculaires responsables des propriétés migratoires des gliomes [Texte imprimé] : rôle et dynamique des jonctions adhérentes dans la migration des astrocytes sains et tumoraux

Malignant glioma is the most common primary brain tumours. It arises from transformed glial cells such as oligodendrocytes precursors or differentiated astrocytes. Due to its ability to broadly infiltrate the brain parenchyma it remains resistant to current therapy and thus bears a very bad prognosis. My PhD project aims at studying the molecular mechanisms involved in glioma invasivity. Transcriptomic analysis of 130 gliomas revealed a sharp decrease in adherens-junction's molecules expression in the most aggressive tumours, the glioblastoma. This alteration of adherens junction proteins in normal and transformed astrocytes is sufficient to increase migration speed and cell propagation in 3D experiments. I then investigated on how the adherens junctions perturbation could affect collective cell migration and found that p120ctn, the major regulator of cadherin stability; is involved in the control of N-cadherin trafficking through its phosphorylation status. Indeed, p120ctn spatially regulates N-cadherin polarized recycling during collective cell migration and its alteration leads to increased astrocyte and glioma cell migration. More precisely, p120ctn, the major regulator of adherens junction stability, was shown to be inversely correlated to the invasive capacity of glioma. A systematic study of p120ctn expression level in a bigger group of patients carefully supervised for their tumor progression is on the way and hopefully will show that p120ctn is a reliable invasivity marker for glioma.Les gliomes sont les tumeurs cérébrales primitives les plus fréquentes. Dérivant des cellules gliales et majoritairement des astrocytes, les gliomes malins évoluent rapidement et sont associés à un très mauvais pronostic, en partie causé par leur nature invasive. Les cellules de gliomes infiltrent activement le parenchyme cérébral, ce qui leur permet d'échapper aux thérapies focales (chirurgie et radiothérapie), et de donner naissance à de nouveaux foyers tumoraux au voisinage direct ou à distance de la tumeur initiale. En analysant le transcriptome de plus de 130 gliomes de différents grades et en me focalisant uniquement sur les variations d'expression de gènes connus pour être impliqués dans la migration, l'invasion, l'adhérence et la polarité astrocytaire, j'ai mis en évidence une altération des jonctions adhérentes dans les gliomes et suggéré une corrélation inverse entre le niveau de la p120ctn et l'invasivité des gliomes in vitro et in vivo.. En contrôlant une boucle de recyclage inédite de la N-cadhérine dans les cellules en migration, la p120ctn régule spatialement les forces d'adhérence intercellulaire, et assure une migration collective dirigée. L'altération de sa fonction dans les astrocytes sains entraîne une augmentation de la dispersion des cellules, la perturbation de leur directionnalité et in fine une augmentation de leur vitesse de migration ; des caractéristiques identiques aux cellules de gliomes en migration. L'ensemble de ces résultats définit la p120ctn comme une nouvelle cible thérapeutique potentielle pour le traitement des gliomes diffus et comme un potentiel marqueur de l'invasivité des gliomes

Switching states: dynamic remodelling of polarity complexes as a toolkit for cell polarization

International audiencePolarity is defined by the segregation of cellular components along a defined axis. To polarize robustly, cells must be able to break symmetry and subsequently amplify these nascent asymmetries. Finally, asymmetric localization of signaling molecules must be translated into functional regulation of downstream effector pathways. Central to these behaviors are a diverse set of cell polarity networks. Within these networks, molecules exhibit varied behaviors, dynamically switching among different complexes and states, active versus inactive, bound versus unbound, immobile versus diffusive. This ability to switch dynamically between states is intimately connected to the ability of molecules to generate asymmetric patterns within cells. Focusing primarily on polarity pathways governed by the conserved PAR proteins, we discuss strategies enabled by these dynamic behaviors that are used by cells to polarize. We highlight not only how switching between states is linked to the ability of polarity proteins to localize asymmetrically, but also how cells take advantage of ‘state switching’ to regulate polarity in time and space