NCAM180 Regulates Ric8A Membrane Localization and Potentiates β-Adrenergic Response

Cooperation between receptors allows integrated intracellular signaling leading to appropriate physiological responses. The Neural Cell Adhesion Molecule (NCAM) has three main isoforms of 120, 140 and 180 kDa, with adhesive and signaling properties, but their respective functions remains to be fully identified. Here we show that the human NCAM180 intracellular domain is a novel interactor of the human guanosine exchange factor (GEF) Ric8A using the yeast two hybrid system and immunoprecipitation. Furthermore, NCAM, Ric8A and Gαs form a tripartite complex. Colocalization experiments by confocal microscopy revealed that human NCAM180 specifically induces the recruitment of Ric8A to the membrane. In addition, using an in vitro recombinant system, and in vivo by comparing NCAM knock-out mouse brain to NCAM heterozygous and wild type brains, we show that NCAM expression dose dependently regulates Ric8A redistribution in detergent resistent membrane microdomains (DRM). Previous studies have demonstrated essential roles for Ric8 in Gα protein activity at G protein coupled receptors (GPCR), during neurotransmitter release and for asymmetric cell division. We observed that inhibition of Ric8A by siRNA or its overexpression, decreases or increases respectively, cAMP production following β-adrenergic receptor stimulation. Furthermore, in human HEK293T recombinant cells, NCAM180 potentiates the Gαs coupled β-adrenergic receptor response, in a Ric8A dependent manner, whereas NCAM120 or NCAM140 do not. Finally, in mouse hippocampal neurons expressing endogenously NCAM, NCAM is required for the agonist isoproterenol to induce cAMP production, and this requirement depends on Ric8A. These data illustrate a functional crosstalk between a GPCR and an IgCAM in the nervous system

Dynamic quantitative intravital imaging of glioblastoma progression reveals a lack of correlation between tumor growth and blood vessel density

International audienceThe spatiotemporal and longitudinal monitoring of cellular processes occurring in tumors is critical for oncological research. We focused on glioblastoma multiforme (GBM), an untreatable highly vascularized brain tumor whose progression is thought to critically depend on the oxygen and metabolites supplied by blood vessels. We optimized protocols for orthotopic GBM grafting in mice that were able to recapitulate the biophysical constraints normally governing tumor progression and were suitable for intravital multiphoton microscopy. We repeatedly imaged tumor cells and blood vessels during GBM development. We established methods for quantitative correlative analyses of dynamic imaging data over wide fields in order to cover the entire tumor. We searched whether correlations existed between blood vessel density, tumor cell density and proliferation in control tumors. Extensive vascular remodeling and the formation of new vessels accompanied U87 tumor cell growth, but no strong correlation was found between local cell density and the extent of local blood vessel density irrespective of the tumor area or time points. The technique moreover proves useful for comparative analysis of mice subjected either to Bevacizumab anti-angiogenic treatment that targets VEGF or to AMD3100, an antagonist of CXCR4 receptor. Bevacizumab treatment massively reduced tumoral vessel densities but only transiently reduced U87 tumor growth rate. Again, there was no correlation between local blood vessel density and local cell density. Moreover, Bev applied only prior to tumor implantation inhibited tumor growth to the same extent as post-grafting treatment. AMD3100 achieved a potent inhibition of tumor growth without significant reduction in blood vessel density. These results indicate that in the brain, in this model, tumor growth can be sustained without an increase in blood vessel density and suggest that GBM growth is rather governed by stromal properties

Chaetozone carpenteri, McIntosh, 1911 from the Mediterranean Sea and records of other bi-tentaculate Cirratulids

Many species of Cirratulidae have been recorded from the Mediterranean Sea since the descriptions and figures of the Naples fauna in one of the first comprehensive studies of polychaetes by delle Chiaje, 1823–3022. Chiaje, SD. 1823–30. Memorie sulla storia e notomia degli animali senza vertebre del Regno di Napoli, Vol.4, 109–214 . Napoli: Dalla stamperia de’ Fratelli Fernandes. View all references. This original publication included only multi-tentaculate cirratulids and what we would now identify as Cirriformia and Cirratulus. Since delle Chiaje's publication, 25 bi-tentaculate taxa have been recorded from the Mediterranean. During recent sampling programmes Chaetozone carpenteri McIntosh, 191155. McIntosh, WC. 1911. Notes from the Gatty Marine Laboratory, St Andrews. No. XXXII . Annals and Magazine of Natural History, Series, 8(7): 145–173. View all references, a bi-tentaculate cirratulid, has been recorded from several Mediterranean sites and is redescribed. All records of C. setosa will need to be re-examined as they may have been misidentified

Contribution of the Neural Cell Adhesion Molecule to Neuronal and Synaptic Plasticity

The neural cell adhesion molecule (NCAM) and its polysialylated form PSA-NCAM contribute to many aspects of the development and plasticity of the central nervous system. This includes mechanisms of cell differentiation and migration, neurite outgrowth, establishment of specific patterns of synaptic connections, synaptic plasticity and long-term potentiation. How NCAM and PSA-NCAM contribute to regulate all these different mechanisms remains essentially unknown. Adhesive properties appear to be important, but recent studies also point to possible interactions between NCAM and PSA-NCAM with intracellular signalling cascades that are essential to biological functions. Some of these mechanisms are discussed and a hypothesis is proposed based on the existence of cross-talk between these molecules and signalling pathways mediated by growth factors