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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2371-2380. Prepublished online as a Blood First Edition Paper on May 21, 2007; DOI 10.1182/blood-2006-10-055087. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-10-055087v1 110/7/2371    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kile, B. T. Articles by Justice, M. J. Search for Related Content PubMed PubMed Citation Articles by Kile, B. T. Articles by Justice, M. J. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 30, 2006 Accepted May 16, 2007 Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia Benjamin T. Kile*, Athanasia D. Panopoulos, Roslynn A. Stirzaker, Douglas F. Hacking, Lubna H. Tahtamouni, Tracy A. Willson, Lisa A. Mielke, Katya J. Henley, Jian-Guo Zhang, Ian P. Wicks, William S. Stevenson, Paquita Nurden, Stephanie S. Watowich, and Monica J. Justice Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States Department of Immunology, MD Anderson Cancer Center, Houston, TX, United States Department of Medical Biology, The University of Melbourne, Parkville, Australia Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia Department of Biological Sciences and Biotechnology, Hashemite University, Zarqua, Jordan Cancer and Hematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia Autoimmunity and Transplantation, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia Centre de Reference des Pathologies Plaquiettaires, Plateforme Technologique et d'Innovation Biomedicale, Hopital Xavier Arnozan, Pessac, France Graduate School of Biomedical Sciences, University of Texas, Houston, TX, United States * Corresponding author; email: kile{at}wehi.edu.au. A pivotal mediator of actin dynamics is the protein cofilin, which promotes filament severing and depolymerization, facilitating the breakdown of existing filaments, and the enhancement of filament growth from newly created barbed ends. It does so in concert with actin interacting protein 1 (Aip1), which serves to accelerate cofilin's activity. While progress has been made in understanding its biochemical functions, the physiological processes the cofilin/Aip1 complex regulates, particularly in higher organisms, are yet to be determined. We have generated an allelic series for WD40 repeat protein 1 (Wdr1), the mammalian homolog of Aip1, and report that reductions in Wdr1 function produce a dramatic phenotype gradient. While severe loss-of-function at the Wdr1 locus causes embryonic lethality, mice carrying hypomorphic alleles develop macrothrombocytopenia and autoinflammatory disease. Macrothrombocytopenia is the result of megakaryocyte maturation defects, which leads to a failure of normal platelet shedding. Autoinflammatory disease, which is bone marrow-derived yet non-lymphoid in origin, is characterised by a massive infiltration of neutrophils into inflammatory lesions. Cytoskeletal responses are impaired in Wdr1 mutant neutrophils. These studies establish an essential requirement for Wdr1 in megakaryocytes and neutrophils, indicating that cofilin-mediated actin dynamics are critically important to the development and function of both cell types. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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