International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


ORAL PRESENTATION

TUESDAY OCTOBER 19

4.30pm - 4.45pm

INFLAMMATORY DISEASE AND ABORTIVE PLATELET SHEDDING CAUSED BY A MUTATION IN A PIVOTAL MODULATOR OF ACTIN DYNAMICS IN THE REDEARS MOUSE

Kile BT2, Woodward LS1, Justice MJ1

1 Baylor College of Medicine, Houston, United States, 2 The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

Recently identified in a balancer chromosome mutagenesis screen, the redears mouse is an intriguing model of inflammatory disease and thrombocytopenia. Animals homozygous for the redears (rd) mutation develop spontaneous inflammatory lesions of the ears and tail characterised by necrosis, edema, epithelial thickening and leukocyte infiltration. Neutrophils are the predominant infiltrating cell, and neutrophilia is observed in the peripheral blood and spleen. Chemotaxis and apoptosis are perturbed in rd/rd neutrophils suggesting these cells are playing a key role in driving the inflammatory process. Unexpectedly, blood platelet numbers are dramatically reduced in rd/rd animals, and a thorough analysis of platelet biogenesis confirms this is the result of defects in the platelet precursor cell, the megakaryocyte. rd/rd megakaryocytes undergo an abnormal maturation, characterised by gross morphological abnormalities, increased ploidy and abortive platelet shedding. We have identified a mutation in a gene related to the yeast actin-interacting protein Aip1, in rd/rd mice.  While its exact role remains controversial, Aip1 interacts with, and increases the activity of cofilin, a key regulator of actin polymerisation. Our data suggests the rd mutation is hypomorphic, and confirm that actin dynamics are dysregulated in rd/rd neutrophils. This provides an explanation for chemotactic deficiencies, and in conjunction with recent evidence implicating cofilin and other actin regulators in the initiation of apoptosis, suggests that this protein might play an essential role in neutrophil cell death. The massive cytoplasmic reorganisation that is required for megakaryocyte maturation and platelet shedding has long been assumed to depend on the actin cytoskeleton. Intriguingly, recent studies suggest the process is caspase-dependent, and represents a form of ‘para-apoptosis’. Thus, the redears mouse not only provides the first in vivo demonstration of the critical role of the actin cytoskeleton in megakaryocyte development and platelet production, but also represents a unique reagent to examine the relationship between actin dynamics, cellular maturation, inflammation and apoptosis.

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