αPIX RhoGEF Supports Positive Selection by Restraining Migration and Promoting Arrest of Thymocytes

Korthals, Mark; Schilling, Kerstin; Reichardt, Peter; Mamula, Dejan; Schlüter, Thomas; Steiner, Michael; Langnäse, Kristina; Thomas, Ulrike; Gundelfinger, Eckart D.; Premont, Richard T.; Tedford, Kerry; Fischer, Klaus–Dieter

doi:10.4049/jimmunol.1302585

Cited by 10 publications

(17 citation statements)

References 41 publications

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“…To this end, we used lymphocytes with a mutation in Arhgef6 . T cells and B cells lacking this cytoskeleton regulator have reduced cell–cell contacts and migrate faster than wild-type cells in transwell assays and in thymic lobes, consistent with a defect in adhesion 23 , 24 . We first quantified the numbers of Arhgef6 −/− MZBs by flow cytometry and found an ~50% increase in their numbers in mice of all ages (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 74%

“…One defining feature of Arhgef6 −/− lymphocytes is increased speed 24 . Interestingly, this phenotype may also explain the elevated MZB numbers in Arhgef6 −/− mice: increased Arhgef6 −/− T-cell speed is linked to defective cell–cell contacts 24 , and MZB cell–cell contacts with invariant natural killer T (iNKT) cells are required to inhibit MZB numbers 30 . Thus, increased Arhgef6 −/− MZB speed may reduce contacts with iNKT, leading to increased numbers.…”

Section: Discussionmentioning

confidence: 99%

“…For transwell migration assays, 5 µm pore size membranes (Corning Costar) were coated with 10 µg ml −1 recombinant mouse ICAM-1/CD54 Fc (R&D Systems) and blocked with 2% BSA. Migration of cells to S1P and CXCL13 (R&D) was analyzed as described (Korthals et al 24 ).…”

Section: Methodsmentioning

confidence: 99%

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The opposing forces of shear flow and sphingosine-1-phosphate control marginal zone B cell shuttling

et al. 2017

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Splenic marginal zone B cells (MZB) shuttle between the blood-filled marginal zone for antigen collection and the follicle for antigen delivery. However, it is unclear how MZBs migrate directionally from the marginal zone to the follicle. Here, we show that murine MZBs migrate up shear flow via the LFA-1 (αLβ2) integrin ligand ICAM-1, but adhere or migrate down the flow via the VLA-4 integrin (α4β1) ligand VCAM-1. MZBs lacking Arhgef6 (Pak-interacting exchange factor (αPIX)) or functional LFA-1 are impaired in shuttling due to mislocalization toward the VCAM-1-rich red pulp. Sphingosine-1-phosphate (S1P) signaling through the S1PR3 receptor inhibits MZB migration up the flow, and deletion of S1pr3 in Arhgef6 −/− mice rescues mislocalized MZBs. These findings establish shear flow as a directional cue for MZB migration to the follicle, and define S1PR3 and VCAM-1 as counteracting forces that inhibit this migration.

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Section: Resultsmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

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The opposing forces of shear flow and sphingosine-1-phosphate control marginal zone B cell shuttling

et al. 2017

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“…Therefore, optimal intrathymic trafficking of DP cells is considered to be critical for positive selection. Indeed, mutant mice that lacked signaling molecules that regulate cell motility, such as GIT2 or aPIX RhoGEF, had abnormal DP cell trafficking and impaired positive selection (7,8). During the transition of positively selected DP to CD4 or CD8 single-positive (SP) cells, thymocytes upregulate the expression of chemokine receptors and acquire a high trafficking capability as they migrate from the cortex into the medulla (1,9).…”

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confidence: 99%

Sema3e/Plexin D1 Modulates Immunological Synapse and Migration of Thymocytes by Rap1 Inhibition

Ueda

Kondo

Ozawa

et al. 2016

The Journal of Immunology

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Regulation of thymocyte trafficking plays an important role during thymic selection, but our understanding of the molecular mechanisms underlying these processes is limited. In this study, we demonstrated that class III semaphorin E (sema3e), a guidance molecule during neural and vascular development, directly inhibited Rap1 activation and LFA-1–dependent adhesion through the GTPase-activating protein activity of plexin D1. Sema3e inhibited Rap1 activation of thymocytes in response to chemokines and TCR stimulation, LFA-mediated adhesion, and T cell–APC interactions. Immunological synapse (IS) formation in mature thymocytes on supported lipid bilayers was also attenuated by sema3e. Impaired IS formation was associated with reduced Rap1 activation on the contact surface and cell periphery. Moreover, a significant increase of CD4+ thymocytes was detected in the medulla of mice with T cell lineage–specific deletion of plexin D1. Two-photon live imaging of thymic explants and slices revealed enhanced Rap1 activation and migration of CD69+ double-positive and single-positive cells with plexin D1 deficiency. Our results demonstrate that sema3e/plexin D1 modulates IS formation and Ag-scanning activities of thymocytes within thymic tissues.

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“…At the molecular level, a significant decrease in active RAC1 and CDC42, but not RhoA, was observed in the brain of Arhgef6 knockout mice ( Ramakers et al, 2012 ). Besides the brain, loss of ARHGEF6 was also shown to affect the immune system ( Missy et al, 2008 ; Korthals et al, 2014 ). However, the role of ARHGEF6 in the auditory system remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in Mice

Zhu

Cheng

Wang

et al. 2018

Front. Mol. Neurosci.

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ARHGEF6 belongs to the family of guanine nucleotide exchange factors (GEFs) for Rho GTPases, and it specifically activates Rho GTPases CDC42 and RAC1. Arhgef6 is the X-linked intellectual disability gene also known as XLID46, and clinical features of patients carrying Arhgef6 mutations include intellectual disability and, in some cases, sensorineural hearing loss. Rho GTPases act as molecular switches in many cellular processes. Their activities are regulated by binding or hydrolysis of GTP, which is facilitated by GEFs and GTPase-activating proteins, respectively. RAC1 and CDC42 have been shown to play important roles in hair cell (HC) stereocilia development. However, the role of ARHGEF6 in inner ear development and hearing function has not yet been investigated. Here, we found that ARHGEF6 is expressed in mouse cochlear HCs, including the HC stereocilia. We established Arhgef6 knockdown mice using the clustered regularly interspaced short palindromic repeat-associated Cas9 nuclease (CRISPR-Cas9) genome editing technique. We showed that ARHGEF6 was indispensable for the maintenance of outer hair cell (OHC) stereocilia, and loss of ARHGEF6 in mice caused HC stereocilia deficits that eventually led to progressive HC loss and hearing loss. However, the loss of ARHGEF6 did not affect the synapse density and did not affect the mechanoelectrical transduction currents in OHCs at postnatal day 3. At the molecular level, the levels of active CDC42 and RAC1 were dramatically decreased in the Arhgef6 knockdown mice, suggesting that ARHGEF6 regulates stereocilia maintenance through RAC1/CDC42.

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αPIX RhoGEF Supports Positive Selection by Restraining Migration and Promoting Arrest of Thymocytes

Cited by 10 publications

References 41 publications

The opposing forces of shear flow and sphingosine-1-phosphate control marginal zone B cell shuttling

The opposing forces of shear flow and sphingosine-1-phosphate control marginal zone B cell shuttling

Sema3e/Plexin D1 Modulates Immunological Synapse and Migration of Thymocytes by Rap1 Inhibition

Loss of ARHGEF6 Causes Hair Cell Stereocilia Deficits and Hearing Loss in Mice

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