Publication Date

10-1-2007

Journal

Blood. 2007 October 1; 110(7): 2371–2380. Prepublished online 2007 May 21. doi: 10.1182/blood-2006-10-055087.

Abstract

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 physiologic 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, macrothrombocytopenia and autoinflammatory disease develop in mice carrying hypomorphic alleles. Macrothrombocytopenia is the result of megakaryocyte maturation defects, which lead to a failure of normal platelet shedding. Autoinflammatory disease, which is bone marrow-derived yet nonlymphoid in origin, is characterized 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.

Keywords

Actin Depolymerizing Factors, Alleles, Amino Acid Sequence, Animals, Blood Platelets, Cell Differentiation, Cell Movement, Conserved Sequence, Humans, Inflammation, Megakaryocytes, Mice, Mice, Knockout, Microfilament Proteins, Microscopy, Electron, Transmission, Molecular Sequence Data, Mutation, Neutrophils, Sequence Alignment, Thrombocytopenia

Comments

PMC1988957

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