title: αPIX RhoGEF supports positive selection by restraining migration and promoting arrest of thymocytes.
abstract: Thymocytes mature in a series of stages by migrating through specific areas of the thymus and interacting with other cells to receive the necessary developmental signals; however, little is known about the molecular mechanisms governing this migration. We report that murine thymocytes with a knockout mutation in α-PAK (p21-activated kinase)-interacting exchange factor (PIX; Arhgef6), an activator of Rho GTPases, showed greatly increased motility and altered morphology in two-dimensional migration on ICAM-1. αPIX was also required for efficient positive selection, but not negative selection, of thymocytes. TCR signaling was normal in αPix(-) thymocytes, indicating that the effects of αPIX on positive selection are largely independent of TCR signaling. αPix(-) thymocytes also paused less during migration in the thymic cortex, interacted less with ICAM-1 coated beads, and could overcome TCR stop signals, consistent with defective scanning behavior. These results identify αPIX as a regulator of thymocyte migration and subsequent arrest that is linked to positive selection.
authors.affiliation: Department of Functional Genomics and Medical Toponomics, Otto-von-Guericke-University, Medical Faculty, Magdeburg 39120, Germany;
authors.forename: Mark
authors.initials: M
authors.lastname: Korthals
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schilling
authors.forename: Peter
authors.initials: P
authors.lastname: Reichardt
authors.forename: Dejan
authors.initials: D
authors.lastname: Mamula
authors.forename: Thomas
authors.initials: T
authors.lastname: Schlüter
authors.forename: Michael
authors.initials: M
authors.lastname: Steiner
authors.forename: Kristina
authors.initials: K
authors.lastname: Langnäse
authors.forename: Ulrich
authors.initials: U
authors.lastname: Thomas
authors.forename: Eckart
authors.initials: E
authors.lastname: Gundelfinger
authors.forename: Richard T
authors.initials: RT
authors.lastname: Premont
authors.forename: Kerry
authors.initials: K
authors.lastname: Tedford
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Fischer
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D036641:Microscopy, Fluorescence, Multiphoton; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D060168:Thymocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: C576604:Arhgef6 protein, mouse; D008164:Luminescent Proteins; D011948:Receptors, Antigen, T-Cell; D064067:Rho Guanine Nucleotide Exchange Factors; D018799:Intercellular Adhesion Molecule-1