title: Wiskott-Aldrich syndrome protein (WASP) and N-WASP are critical for peripheral B-cell development and function.
abstract: The Wiskott-Aldrich syndrome protein (WASP) is a key cytoskeletal regulator of hematopoietic cells. Although WASP-knockout (WKO) mice have aberrant B-cell cytoskeletal responses, B-cell development is relatively normal. We hypothesized that N-WASP, a ubiquitously expressed homolog of WASP, may serve some redundant functions with WASP in B cells. In the present study, we generated mice lacking WASP and N-WASP in B cells (conditional double knockout [cDKO] B cells) and show that cDKO mice had decreased numbers of follicular and marginal zone B cells in the spleen. Receptor-induced activation of cDKO B cells led to normal proliferation but a marked reduction of spreading compared with wild-type and WKO B cells. Whereas WKO B cells showed decreased migration in vitro and homing in vivo compared with wild-type cells, cDKO B cells showed an even more pronounced decrease in the migratory response in vivo. After injection of 2,4,6-trinitrophenol (TNP)-Ficoll, cDKO B cells had reduced antigen uptake in the splenic marginal zone. Despite high basal serum IgM, cDKO mice mounted a reduced immune response to the T cell-independent antigen TNP-Ficoll and to the T cell-dependent antigen TNP-keyhole limpet hemocyanin. Our results reveal that the combined activity of WASP and N-WASP is required for peripheral B-cell development and function.
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02115, USA. lisa.westerberg@ki.se
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Westerberg
authors.forename: Carin
authors.initials: C
authors.lastname: Dahlberg
authors.forename: Marisa
authors.initials: M
authors.lastname: Baptista
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Moran
authors.forename: Cynthia
authors.initials: C
authors.lastname: Detre
authors.forename: Marton
authors.initials: M
authors.lastname: Keszei
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Eston
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000502:physiology*; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002633:Chemotaxis; D005362:Ficoll / Q000031:analogs & derivatives / Q000494:pharmacology; D005434:Flow Cytometry; D006410:Hematopoiesis / Q000502:physiology; D007114:Immunization; D007124:Immunoenzyme Techniques; D019426:Integrases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D014301:Trinitrobenzenes / Q000494:pharmacology; D051316:Wiskott-Aldrich Syndrome Protein / Q000502:physiology*; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000502:physiology*
chemical_list: C020529:TNP-ficoll; D014301:Trinitrobenzenes; C495768:Was protein, mouse; C495772:Wasl protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D005362:Ficoll; C045073:Cre recombinase; D019426:Integrases