210 research outputs found
Function and regulation of Rnd proteins in cortical projection neuron migration
The mammalian cerebral cortex contains a high variety of neuronal subtypes that acquire precise spatial locations and form long or short-range connections to establish functional neuronal circuits. During embryonic development, cortical projection neurons are generated in the areas lining the lateral ventricles and they subsequently undergo radial migration to reach the position of their final maturation within the cortical plate. The control of the neuroblast migratory behavior and the coordination of the migration process with other neurogenic events such as cell cycle exit, differentiation and final maturation are crucial to normal brain development. Among the key regulators of cortical neuron migration, the small GTP binding proteins of the Rho family and the atypical Rnd members play important roles in integrating intracellular signaling pathways into changes in cytoskeletal dynamics and motility behavior. Here we review the role of Rnd proteins during cortical neuronal migration and we discuss both the upstream mechanisms that regulate Rnd protein activity and the downstream molecular pathways that mediate Rnd effects on cell cytoskeleton
Oxygen Tension Modulates Neurite Outgrowth in PC12 Cells Through A Mechanism Involving HIF and VEGF
Cell-based approaches are a promising therapeutic strategy for treating injuries to the nervous system, but the optimal means to promote neurite extension and direct cellular behavior are unclear. Previous studies have examined the behavior of neural-like cells in ambient air (21% oxygen tension), yet these conditions are not representative of the physiological oxygen microenvironment of neural tissues. We hypothesized that neuronal differentiation of a model neural cell line (PC12) could be controlled by modulating local oxygen tension. Compared to ambient conditions, PC12 cells cultured in reduced oxygen exhibited significant increases in neurite extension and total neurite length, with 4% oxygen yielding the highest levels of both indicators. We confirmed neurite extension was mediated through oxygen-responsive mechanisms using small molecules that promote or inhibit HIF-1α stabilization. The hypoxic target gene Vegf was implicated as a neurotrophic factor, as neurite formation at 21% oxygen was mimicked with exogenous VEGF, and a VEGF-neutralizing antibody attenuated neurite formation under reduced oxygen conditions. These findings demonstrate that behavior of neural-like cells is driven by the oxygen microenvironment via VEGF function, and suggest promising approaches for future applications in neural repair
Betacellulin inhibits osteogenic differentiation and stimulates proliferation through HIF-1α
Cellular signaling via epidermal growth factor (EGF) and EGF-like ligands can determine cell fate and behavior. Osteoblasts, which are responsible for forming and mineralizing osteoid, express EGF receptors and alter rates of proliferation and differentiation in response to EGF receptor activation. Transgenic mice over-expressing the EGF-like ligand betacellulin (BTC) exhibit increased cortical bone deposition; however, because the transgene is ubiquitously expressed in these mice, the identity of cells affected by BTC and responsible for increased cortical bone thickness remains unknown. We have therefore examined the influence of BTC upon mesenchymal stem cell (MSC) and pre-osteoblast differentiation and proliferation. BTC decreases the expression of osteogenic markers in both MSCs and pre-osteoblasts; interestingly, increases in proliferation require hypoxia-inducible factor-alpha (HIF-α), as an HIF antagonist prevents BTC-driven proliferation. Both MSCs and pre-osteoblasts express EGF receptors ErbB1, ErbB2, and ErbB3, with no change in expression under osteogenic differentiation. These are the first data that demonstrate an influence of BTC upon MSCs and the first to implicate HIF-α in BTC-mediated proliferation
14-3-3 Proteins Interact with a Hybrid Prenyl-Phosphorylation Motif to Inhibit G Proteins
Signaling through G proteins normally involves conformational switching between GTP- and GDP-bound states. Several Rho GTPases are also regulated by RhoGDI binding and sequestering in the cytosol. Rnd proteins are atypical constitutively GTP-bound Rho proteins, whose regulation remains elusive. Here, we report a high-affinity 14-3-3-binding site at the C terminus of Rnd3 consisting of both the Cys241-farnesyl moiety and a Rho-associated coiled coil containing protein kinase (ROCK)-dependent Ser240 phosphorylation site. 14-3-3 binding to Rnd3 also involves phosphorylation of Ser218 by ROCK and/or Ser210 by protein kinase C (PKC). The crystal structure of a phosphorylated, farnesylated Rnd3 peptide with 14-3-3 reveals a hydrophobic groove in 14-3-3 proteins accommodating the farnesyl moiety. Functionally, 14-3-3 inhibits Rnd3-induced cell rounding by translocating it from the plasma membrane to the cytosol. Rnd1, Rnd2, and geranylgeranylated Rap1A interact similarly with 14-3-3. In contrast to the canonical GTP/GDP switch that regulates most Ras superfamily members, our results reveal an unprecedented mechanism for G protein inhibition by 14-3-3 proteins
Adult-born neurons immature during learning are necessary for remote memory reconsolidation in rats
Memory reconsolidation, the process by which memories are again stabilized after being reactivated, has strengthened the idea that memory stabilization is a highly plastic process. To date, the molecular and cellular bases of reconsolidation have been extensively investigated particularly within the hippocampus. However, the role of adult neurogenesis in memory reconsolidation is unclear. Here, we combined functional imaging, retroviral and chemogenetic approaches in rats to tag and manipulate different populations of rat adult-born neurons. We find that both mature and immature adult-born neurons are activated by remote memory retrieval. However, only specific silencing of the adult-born neurons immature during learning impairs remote memory retrieval-induced reconsolidation. Hence, our findings show that adult-born neurons immature during learning are required for the maintenance and update of remote memory reconsolidation.RÎle de la neurogénÚse hippocampique dans la reconsolidation de la mémoireDissection des mécanismes hypothalamiques impliqués dans la détection du statut nutritionnel et régulation de la prise alimentaire via les interactions entre mTORC1, les mélanocortines et les endocannabinoïdes
Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transition
In the developing mammalian brain, differentiating neurons mature morphologically via neuronal polarity programs. Despite discovery of polarity pathways acting concurrently with differentiation, it's unclear how neurons traverse complex polarity transitions or how neuronal progenitors delay polarization during development. We report that zinc finger and homeobox transcription factor-1 (Zeb1), a master regulator of epithelial polarity, controls neuronal differentiation by transcriptionally repressing polarity genes in neuronal progenitors. Necessity-sufficiency testing and functional target screening in cerebellar granule neuron progenitors (GNPs) reveal that Zeb1 inhibits polarization and retains progenitors in their germinal zone (GZ). Zeb1 expression is elevated in the Sonic Hedgehog (SHH) medulloblastoma subgroup originating from GNPs with persistent SHH activation. Restored polarity signaling promotes differentiation and rescues GZ exit, suggesting a model for future differentiative therapies. These results reveal unexpected parallels between neuronal differentiation and mesenchymal-to-epithelial transition and suggest that active polarity inhibition contributes to altered GZ exit in pediatric brain cancers.National Institute of Neurological Disorders and Stroke grant: (1R01NS066936); March of Dimes Foundation grant: (#1-FY12-455).info:eu-repo/semantics/publishedVersio
Physiological and pathophysiological control of synaptic GluN2B-NMDA receptors by the C-terminal domain of amyloid precursor protein
The amyloid precursor protein (APP) harbors physiological roles at synapses and is central to Alzheimer's disease (AD) pathogenesis. Evidence suggests that APP intracellular domain (AICD) could regulate synapse function, but the underlying molecular mechanisms remain unknown. We addressed AICD actions at synapses, per se, combining in vivo AICD expression, ex vivo AICD delivery or APP knock-down by in utero electroporation of shRNAs with whole-cell electrophysiology. We report a critical physiological role of AICD in controlling GIuN2B-containing NMDA receptors (NMDARs) at immature excitatory synapses, via a transcription-dependent mechanism. We further show that AICD increase in mature neurons, as reported in AD, alters synaptic NMDAR composition to an immature-like GIuN2B-rich profile. This disrupts synaptic signal integration, via over-activation of SK channels, and synapse plasticity, phenotypes rescued by GIuN2B antagonism. We provide a new physiological role for AICD, which becomes pathological upon AICD increase in mature neurons. Thus, AICD could contribute to AD synaptic failure
Transplantation of mesenchymal stem cells in a laryngeal carcinoma patient with radiation myelitis
Study of the radioactive liquid waste treatment by coprecipitation : from modelling to design of new processes
Le procĂ©dĂ© par coprĂ©cipitation est lâun des plus utilisĂ© dans lâindustrie nuclĂ©aire pour le traitement des effluents liquides radioactifs car il peut ĂȘtre appliquĂ© Ă tous les effluents quelque soit leur composition. Ce procĂ©dĂ© consiste Ă former in situ des particules solides par prĂ©cipitation dans le but de capter sĂ©lectivement un ou plusieurs radioĂ©lĂ©ments. Lâobjectif de ce travail de thĂšse est de mettre en Ă©vidence les phĂ©nomĂšnes impliquĂ©s lors de la coprĂ©cipitation dâun Ă©lĂ©ment prĂ©sent en faible concentration. Pour cela, cette Ă©tude propose une nouvelle modĂ©lisation des phĂ©nomĂšnes de coprĂ©cipitation dont lâoriginalitĂ© tient dans la possibilitĂ© de simuler le phĂ©nomĂšne hors Ă©quilibre thermodynamique et Ă lâĂ©chelle dâun rĂ©acteur chimique. Ce modĂšle, couplĂ© avec la rĂ©solution du bilan de population, permet dâidentifier lâinfluence des paramĂštres de procĂ©dĂ©s (dĂ©bits, agitationâŠ) sur la dĂ©contamination. Afin dâĂ©prouver ce nouveau modĂšle, celui-ci est appliquĂ© au traitement, dans les conditions industrielles, du strontium par le sulfate de baryum en rĂ©acteur continu et semi-fermĂ©. A partir de ces simulations, des lois dâĂ©volution de lâefficacitĂ© du traitement en fonction de diffĂ©rents paramĂštres de procĂ©dĂ© (Temps de passage ou dâinjection, agitation, concentration de BaSO4) ont Ă©tĂ© dĂ©gagĂ©es puis vĂ©rifiĂ©es expĂ©rimentalement. Cette Ă©tude permet de dĂ©finir les meilleures conditions de traitement. Trois dispositifs (Ă recyclage, Ă lit fluidisĂ© et rĂ©acteur/dĂ©canteur) permettant dâapprocher ces meilleures conditions ont Ă©tĂ© testĂ©s avec succĂšs. Ceux-ci ouvrent dâimportantes perspectives pour la rĂ©duction de la quantitĂ© de boue produite. Deux brevets ont Ă©tĂ© dĂ©posĂ©s suite Ă ce travailTo decontaminate liquid nuclear wastes, the coprecipitation process is the most commonly used in nuclear field because it can be applied to any type of aqueous effluents whatever their composition may be. This process deals with the in situ precipitation of solid particles to selectively remove one or more radioelements. The aim of this PhD work is to investigate phenomena which take place during the coprecipitation of a trace component. To reach this objective, we have proposed a new modelling of the coprecipitation mechanism. The originality of this new approach lies in the possibility to simulate the phenomenon in non equilibrium conditions and at the reactor scale. This modelling combined with the resolution of the population balance, enable to identify the influence of process parameters (flowrates, stirring speedâŠ) on crystal size and ultimately on decontamination. To test this new modelling, simulations of the coprecipitation of strontium ions with barium sulphate have been performed in continuous and semibatch reactors. Thanks to these simulations, laws of the treatment efficiency variation as a function of several process parameters (mean residence time, stirring speed, BaSO4 concentration) have been determined and experimentally verified. This study leads to the determination of optimal treatment conditions. Three apparatus (recycling apparatus, fluidised bed and reactor/settling tank) providing these optimal conditions have been successfully tested and offered significant outlooks for the reduction of the volume of sludge produced by the process. Two new processes are patent pendin
Dynamique des milieux stratifiés ou tournants : Attracteurs d'ondes axisymétriques, interaction non-linéaire et panaches en rotation
Inertia-gravity waves propagate in stratified and/or rotating media and are of great importance in the geophysical context, particularly in the ocean, due to the transport and the dissipation of the energy injected by tidal forces, and to maintain its stratification. Their peculiar dispersion relation, linking frequency and propagation angle, also makes them an interesting object of study. This relation causes, during the reflection on an inclined slope, the focusing of a wave beam and the rise of structures, called attractors, on which the energy is concentrated. We study numerically by raytracing the conditions of formation of these attractors, already well studied in two dimensions, in a three-dimensional geometry, restricted to the axisymmetric case. An experimental study confirms the formation of these attractors, and their use to reach the weakly non-linear regime. In particular, the resonant triadic instability is observed, with differences between a stratified fluid at rest and a homogeneous rotating fluid, due to the possibility of interaction withstanding wave modes. The presence of the axis of symmetry increases the dissipation in the system and prevents the occurrence of a wave turbulence type of energy cascade. In the ocean, waves can propagate in the form of vertical propagative modes and the stratification isnon-linear. With such a stratification in the laboratory, a mode can interact with itself to form a wave with double the frequency. A final section looks at the dynamics of plumes in a uniform rotating ambient fluid. Under certain conditions, the plume is no longer deviated from its axis but is laminarised to form a cylindrical vortex, like a tornado, which could have consequences for the transport by these plumes.Les ondes gravito-inertielles se propagent dans les milieux stratifiĂ©s et/ou en rotation. Elles ont une importance dans le contexte gĂ©ophysique, notamment dans lâocĂ©an, par leur capacitĂ© Ă transporter et dissiper lâĂ©nergie. Leur relation de dispersion, liant frĂ©quence et angle de propagation, cause lors de la rĂ©flexion sur une pente inclinĂ©e, la focalisation dâun faisceau dâonde et l'apparition de structures, appelĂ©es attracteurs, sur lesquelles lâĂ©nergie est concentrĂ©e. Nous Ă©tudions numĂ©riquement par tracĂ© de rayons les conditions de formation de ces attracteurs, dĂ©jĂ bien Ă©tudiĂ©es en deux dimensions, dans une gĂ©omĂ©trie tridimensionnelle, restreinte au cas axisymĂ©trique. Une Ă©tude expĂ©rimentale confirme la formation de ces attracteurs dans le rĂ©gime linĂ©aire. Dans le rĂ©gime faiblement non-linĂ©aire, lâinstabilitĂ© triadique rĂ©sonnante est observĂ©e, mettant en Ă©vidence des diffĂ©rences entre un fluide stratifiĂ© au repos et un fluide homogĂšne en rotation, celles-ci Ă©tant dues Ă la possibilitĂ© dâinteraction avec des modes dâondes stationnaires. La prĂ©sence de lâaxe de symĂ©trie, augmentant la dissipation dans le systĂšme, empĂȘche lâapparition dâune cascade dâĂ©nergie de type turbulence dâondes. Le rĂŽle d'une stratification non-linĂ©aire dans la formation de modes verticaux super-harmoniques est Ă©tudiĂ©e par superposition et auto-interaction de modes. Une derniĂšre partie sâintĂ©resse Ă la dynamique de panaches dans un milieu uniforme en rotation. Sous certaines conditions, celui-ci nâest plus dĂ©viĂ© de son axe mais est laminarisĂ© pour former un tourbillon cylindrique, tel une tornade, pouvant avoir des consĂ©quences sur le transport par ces panaches
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