Unregulated actin polymerization by WASp causes defects of mitosis and cytokinesis in X-linked neutropenia.

Publisher: Rockefeller University Press Country of Publication: United States NLM ID: 2985109R Publication Model: Print-Electronic Cited Medium: Print ISSN: 0022-1007 (Print) Linking ISSN: 00221007 NLM ISO Abbreviation: J Exp Med Subsets: MEDLINE

Original Publication: New York, NY : Rockefeller University Press

Cytokinesis*/drug effects ; Mitosis*/drug effects; Actins/*metabolism ; Genetic Diseases, X-Linked/*metabolism ; Neutropenia/*metabolism ; Neutropenia/*pathology ; Wiskott-Aldrich Syndrome Protein/*metabolism; Animals ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Nucleus/drug effects ; Cell Nucleus/metabolism ; Cell Proliferation/drug effects ; Chromosome Aberrations ; Chromosomes, Human ; DNA ; Depsipeptides/pharmacology ; Genetic Diseases, X-Linked/pathology ; Green Fluorescent Proteins/metabolism ; Humans ; Mice ; Mutant Proteins/metabolism ; Polyploidy ; Recombinant Fusion Proteins/metabolism ; Transgenes

Specific mutations in the human gene encoding the Wiskott-Aldrich syndrome protein (WASp) that compromise normal auto-inhibition of WASp result in unregulated activation of the actin-related protein 2/3 complex and increased actin polymerizing activity. These activating mutations are associated with an X-linked form of neutropenia with an intrinsic failure of myelopoiesis and an increase in the incidence of cytogenetic abnormalities. To study the underlying mechanisms, active mutant WASp(I294T) was expressed by gene transfer. This caused enhanced and delocalized actin polymerization throughout the cell, decreased proliferation, and increased apoptosis. Cells became binucleated, suggesting a failure of cytokinesis, and micronuclei were formed, indicative of genomic instability. Live cell imaging demonstrated a delay in mitosis from prometaphase to anaphase and confirmed that multinucleation was a result of aborted cytokinesis. During mitosis, filamentous actin was abnormally localized around the spindle and chromosomes throughout their alignment and separation, and it accumulated within the cleavage furrow around the spindle midzone. These findings reveal a novel mechanism for inhibition of myelopoiesis through defective mitosis and cytokinesis due to hyperactivation and mislocalization of actin polymerization.

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United Kingdom WT_ Wellcome Trust; 070613 United Kingdom WT_ Wellcome Trust; BB/E012965/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; G0401026 United Kingdom MRC_ Medical Research Council

0 (Actins)
0 (Depsipeptides)
0 (Mutant Proteins)
0 (Recombinant Fusion Proteins)
0 (Wiskott-Aldrich Syndrome Protein)
0 (enhanced green fluorescent protein)
102396-24-7 (jasplakinolide)
147336-22-9 (Green Fluorescent Proteins)
9007-49-2 (DNA)

Date Created: 20070829 Date Completed: 20071019 Latest Revision: 20220129

20221213

PMC2118706

10.1084/jem.20062324

17724125