Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott–Aldrich syndrome-like platelet defect
Copyright policy )Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott–Aldrich syndrome-like platelet defect
Wiskott-Aldrich syndrome (WAS) is caused by mutations in the WAS gene and is characterized by immunodeficiency, eczema and microthrombocytopenia. The molecular link between WAS mutations and microthrombocytopenia is unknown. Profilin1 (Pfn1) is a key actin-regulating protein that, besides actin, interacts with phosphoinositides and multiple proline-rich proteins, including the WAS protein (WASp)/WASp-interacting protein (WIP) complex. Here we report that mice with a megakaryocyte/platelet-specific Pfn1 deficiency display microthrombocytopenia due to accelerated turnover of platelets and premature platelet release into the bone marrow. Both Pfn1-null mouse platelets and platelets isolated from WAS patients contained abnormally organized and hyperstable microtubules. These results reveal an unexpected function of Pfn1 as a regulator of microtubule organization and point to a previously unrecognized mechanism underlying the platelet formation defect in WAS patients.
- Harvard University United States
- University Medical Center Freiburg Germany
- University of Freiburg Germany
- Brigham and Women's Faulkner Hospital United States
- Jena University Hospital Germany
Blood Platelets, Male, Adolescent, Intracellular Signaling Peptides and Proteins, Infant, Microtubules, Hematopoiesis, Wiskott-Aldrich Syndrome, Cytoskeletal Proteins, Mice, Profilins, Gene Expression Regulation, Bone Marrow, Child, Preschool, Mutation, Animals, Humans, Child, Megakaryocytes, Signal Transduction
Blood Platelets, Male, Adolescent, Intracellular Signaling Peptides and Proteins, Infant, Microtubules, Hematopoiesis, Wiskott-Aldrich Syndrome, Cytoskeletal Proteins, Mice, Profilins, Gene Expression Regulation, Bone Marrow, Child, Preschool, Mutation, Animals, Humans, Child, Megakaryocytes, Signal Transduction
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