{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T19:46:11Z","timestamp":1791056771286,"version":"4.1.0"},"reference-count":48,"publisher":"Rockefeller University Press","issue":"9","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2007,9,3]]},"abstract":"<jats:p>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 WASpI294T 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.<\/jats:p>","DOI":"10.1084\/jem.20062324","type":"journal-article","created":{"date-parts":[[2007,8,28]],"date-time":"2007-08-28T00:25:38Z","timestamp":1188260738000},"page":"2213-2224","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":145,"title":["Unregulated actin polymerization by WASp causes defects of mitosis and cytokinesis in X-linked neutropenia"],"prefix":"10.1084","volume":"204","author":[{"given":"Dale A.","family":"Moulding","sequence":"first","affiliation":[{"name":"1Wolfson Centre for Gene Therapy of Childhood Disease and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Blundell","sequence":"additional","affiliation":[{"name":"1Wolfson Centre for Gene Therapy of Childhood Disease and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Spiller","sequence":"additional","affiliation":[{"name":"3Centre for Cell Imaging, School of Biological Sciences, Bioscience Research Building, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.H.","family":"White","sequence":"additional","affiliation":[{"name":"3Centre for Cell Imaging, School of Biological Sciences, Bioscience Research Building, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giles O.","family":"Cory","sequence":"additional","affiliation":[{"name":"4Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"Calle","sequence":"additional","affiliation":[{"name":"5Randall Division of Cell & Molecular Biophysics, King's College London, London SE1 1UL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Kempski","sequence":"additional","affiliation":[{"name":"2Molecular Haematology Unit, UCL Institute of Child Health, University College London, London WC1N 1EH, UK"},{"name":"6Department of Haematology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo","family":"Sinclair","sequence":"additional","affiliation":[{"name":"1Wolfson Centre for Gene Therapy of Childhood Disease and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phil J.","family":"Ancliff","sequence":"additional","affiliation":[{"name":"6Department of Haematology and"},{"name":"7Department of Immunology, Great Ormond Street Hospital, London WC1N 3JH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Kinnon","sequence":"additional","affiliation":[{"name":"1Wolfson Centre for Gene Therapy of Childhood Disease and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth E.","family":"Jones","sequence":"additional","affiliation":[{"name":"5Randall Division of Cell & Molecular Biophysics, King's College London, London SE1 1UL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian J.","family":"Thrasher","sequence":"additional","affiliation":[{"name":"1Wolfson Centre for Gene Therapy of Childhood Disease and"},{"name":"7Department of Immunology, Great Ormond Street Hospital, London WC1N 3JH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2007,8,27]]},"reference":[{"key":"2023072516075369900_BIB1","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/S0960-9822(98)00015-3","volume":"8","year":"1998","journal-title":"Curr. 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