Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott–Aldrich syndrome-like platelet defect

• Published in: Nature communications Vol. 5; no. 1; p. 4746
• Main Authors: Bender, Markus, Stritt, Simon, Nurden, Paquita, van Eeuwijk, Judith M. M., Zieger, Barbara, Kentouche, Karim, Schulze, Harald, Morbach, Henner, Stegner, David, Heinze, Katrin G., Dütting, Sebastian, Gupta, Shuchi, Witke, Walter, Falet, Hervé, Fischer, Alain, Hartwig, John H., Nieswandt, Bernhard
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.09.2014; Nature Publishing Group
• Subjects: 13/106; 13/31; 13/51; 14; 14/1; 14/19; 14/28; 14/69; 631/443/592/1339; 64/60; 692/420/2489/144; 692/699/1541; 82/29; Adolescent; Animals; Blood platelets; Blood Platelets - metabolism; Blood Platelets - pathology; Bone marrow; Bone Marrow - metabolism; Bone Marrow - pathology; Child; Child, Preschool; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Gene Expression Regulation; Hematopoiesis; Hospitals; Humanities and Social Sciences; Humans; Infant; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Male; Megakaryocytes - metabolism; Megakaryocytes - pathology; Mice; Microtubules - metabolism; Microtubules - pathology; multidisciplinary; Mutation; Pediatrics; Profilins - deficiency; Profilins - genetics; Proteins; Science; Science (multidisciplinary); Signal Transduction; Thrombocytopenia; Wiskott-Aldrich Syndrome - genetics; Wiskott-Aldrich Syndrome - metabolism; Wiskott-Aldrich Syndrome - pathology; Wiskott-Aldrich Syndrome Protein - genetics; Wiskott-Aldrich Syndrome Protein - metabolism; France; Germany
• DOI: 10.1038/ncomms5746
• ISSN: 2041-1723

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. Patients with mutations in the gene encoding the cytoskeleton regulator WAS have platelet defects. Here the authors show that the WAS-binding protein, Profilin1, is essential for platelet formation in mice, and that its deficiency reproduces the bleeding disorder of patients with WAS mutations.