Modelling adhesion-independent cell migration

A two-dimensional mathematical model for cells migrating without adhesion capabilities is presented and analyzed. Cells are represented by their cortex, which is modelled as an elastic curve, subject to an internal pressure force. Net polymerization or depolymerization in the cortex is modelled via local addition or removal of material, driving a cortical flow. The model takes the form of a fully nonlinear degenerate parabolic system. An existence analysis is carried out by adapting ideas from the theory of gradient flows. Numerical simulations show that these simple rules can account for the behavior observed in experiments, suggesting a possible mechanical mechanism for adhesion-independent motility.Comment: 22 pages and 9 figure

IgM's exit route

The release of IgM is the first line of an antibody response and precedes the generation of high affinity IgG in germinal centers. Once secreted by freshly activated plasmablasts, IgM is released into the efferent lymph of reactive lymph nodes as early as 3 d after immunization. As pentameric IgM has an enormous size of 1,000 kD, its diffusibility is low, and one might wonder how it can pass through the densely lymphocyte-packed environment of a lymph node parenchyma in order to reach its exit. In this issue of JEM, Thierry et al. show that, in order to reach the blood stream, IgM molecules take a specific micro-anatomical route via lymph node conduits

Modelling adhesion-independent cell migration

International audienceA two-dimensional mathematical model for cells migrating without adhesion capabilities is presented and analyzed. Cells are represented by their cortex, which is modelled as an elastic curve, subject to an internal pressure force. Net polymerization or depoly-merization in the cortex is modelled via local addition or removal of material, driving a cortical flow. The model takes the form of a fully nonlinear degenerate parabolic system. An existence analysis is carried out by adapting ideas from the theory of gradient flows. Numerical simulations show that these simple rules can account for the behavior observed in experiments, suggesting a possible mechanical mechanism for adhesion-independent motility

Diversified actin protrusions promote environmental exploration but are dispensable for locomotion of leukocytes

Most migrating cells extrude their front by the force of actin polymerization. Polymerization requires an initial nucleation step, which is mediated by factors establishing either parallel filaments in the case of filopodia or branched filaments that form the branched lamellipodial network. Branches are considered essential for regular cell motility and are initiated by the Arp2/3 complex, which in turn is activated by nucleation-promoting factors of the WASP and WAVE families. Here we employed rapid amoeboid crawling leukocytes and found that deletion of the WAVE complex eliminated actin branching and thus lamellipodia formation. The cells were left with parallel filaments at the leading edge, which translated, depending on the differentiation status of the cell, into a unipolar pointed cell shape or cells with multiple filopodia. Remarkably, unipolar cells migrated with increased speed and enormous directional persistence, while they were unable to turn towards chemotactic gradients. Cells with multiple filopodia retained chemotactic activity but their migration was progressively impaired with increasing geometrical complexity of the extracellular environment. These findings establish that diversified leading edge protrusions serve as explorative structures while they slow down actual locomotion

Rôle du complexe de polarité Cde42/PAR dans la polarisation, l'apprêtement et la présentation de l'antigène par les lymphocytes B

L'activation des Lymphocytes B repose sur la reconnaissance spécifique de PAg par le BCR, présenté in vivo par d'autres APCs, et conduit à la formation d'une synapse immunologique qui permet Pinternalisation l'Ag et son apprêtement en peptides associés aux molécules du CMHII. Ces complexes CMHII-peptides sont ensuite présentés aux lymphocytes T auxiliaires CD4+. Cette étape permet l'activation et la différentiation des LB en cellules productrices d'anticorps de haute affinité. Cette thèse identifie Cdc42 et le complexe de polarité PAR comme étant des régulateurs essentiels de la polarisation du LB. C'est le premier travail qui démontre la réorientation du centre organisateur des microtubules (MTOC) et des lysosomes contenant le CMHII vers le site d'internalisation de l'Ag, et cette polarisation est essentielle pour la présenation de l'Ag aux lymphocytes T. La polarisation du MTOC vers le site d'interaction avec l'Ag dépend de la GTPase Cdc42, qui est activée sous l'engagement du BCR, et est essentielle à l'apprêtement et la présentation de l'antigène par les LB. Par ailleurs, nous montrons que de Cdc42 est essentielle à l'activation de la kinase aPKCÇ du complexe de polarité PAR en réponse à l'interaction BcR-Ag. L'inhibition de l'expression de Cdc42 ou de aPKCÇ induit un défaut de polarisation du MTOC et des lysosomes vers l'Ag qui conduit à une réduction de l'apprêtement de l'Ag. Enfin, cette thèse montre aussi que la sous-unité Par3 du complexe PAR se concentre à la synapse immunologique, où il agit de concert avec la dynéine pour permettre la polarisation du MTOC à a synapse qui est essentielle pour Pinternalisation de PAg et sa présentation aux lymphocytes T auxiliaires. Ces résultats indiquent que, dans les lymphocytes B, l'activation du BCR induit la réorganisation du cytosquelette de microtubules sous le contrôle de Cdc42 et PAR, et cette polarisation du MTOC est essentielle pour la convergence des vésicules du CMHII et de PAg qui permet l'apprêtement de la présentation de l'Ag.PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

A de novo frameshift pathogenic variant in TBR1 identified in autism without intellectual disability

International audienceBackground: In order to be able to provide accurate genetic counseling to patients with Autism Spectrum Disorder (ASD), it is crucial to identify correlations between heterogeneous phenotypes and genetic alterations. Among the hundreds of de novo pathogenic variants reported in ASD, single-nucleotide variations and small insertions/deletions were reported in TBR1. This gene encodes a transcription factor that plays a key role in brain development. Pathogenic variants in TBR1 are often associated with severe forms of ASD, including intellectual disability and language impairment. Methods: Adults diagnosed with ASD but without intellectual disability (diagnosis of Asperger syndrome, according to the DSM-IV) took part in a genetic consultation encompassing metabolic assessments, a molecular karyotype and the screening of a panel of 268 genes involved in intellectual disability, ASD and epilepsy. In addition, the patient reported here went through a neuropsychological assessment, structural magnetic resonance imaging and magnetic resonance spectroscopy measurements. Results: Here, we report the case of a young adult male who presents with a typical form of ASD. Importantly, this patient presents with no intellectual disability or language impairment, despite a de novo heterozygous frameshift pathogenic variant in TBR1, leading to an early premature termination codon (c.26del, p.(Pro9Leufs*12)). Conclusion: Based on this case report, we discuss the role of TBR1 in general brain development, language development, intellectual disability and other symptoms of ASD. Providing a detailed clinical description of the individuals with such pathogenic variants should help to understand the genotype-phenotype relationships in ASD

Dendritic cells interpret haptotactic chemokine gradients in a manner governed by signal to noise ratio and dependent on GRK6

Navigation of cells along gradients of guidance cues is a determining step in many developmental and immunological processes. Gradients can either be soluble or immobilized to tissues as demonstrated for the haptotactic migration of dendritic cells (DCs) toward higher concentrations of immobilized chemokine CCL21. To elucidate how gradient characteristics govern cellular response patterns, we here introduce an in vitro system allowing to track migratory responses of DCs to precisely controlled immobilized gradients of CCL21. We find that haptotactic sensing depends on the absolute CCL21 concentration and local steepness of the gradient, consistent with a scenario where DC directionality is governed by the signal-to-noise ratio of CCL21 binding to the receptor CCR7. We find that the conditions for optimal DC guidance are perfectly provided by the CCL21 gradients we measure in vivo. Furthermore, we find that CCR7 signal termination by the G-protein-coupled receptor kinase 6 (GRK6) is crucial for haptotactic but dispensable for chemotactic CCL21 gradient sensing in vitro and confirm those observations in vivo. These findings suggest that stable, tissue-bound CCL21 gradients as sustainable “roads” ensure optimal guidance in vivo