title: Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott-Aldrich syndrome-like platelet defect.
abstract: 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.
authors.affiliation: 1] Department of Experimental Biomedicine, University Hospital, University of Würzburg, Würzburg 97080, Germany [2] Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [3].
authors.forename: Markus
authors.initials: M
authors.lastname: Bender
authors.affiliation: 1] Department of Experimental Biomedicine, University Hospital, University of Würzburg, Würzburg 97080, Germany [2] Rudolf Virchow Centre, University of Würzburg, Würzburg 97080, Germany [3].
authors.forename: Simon
authors.initials: S
authors.lastname: Stritt
authors.affiliation: 1] Department of Experimental Biomedicine, University Hospital, University of Würzburg, Würzburg 97080, Germany [2] Plateforme Technologique d'Innovation Biomédicale, Hôpital Xavier Arnozan, Pessac 33600, France.
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
authors.affiliation: 1] Department of Experimental Biomedicine, University Hospital, University of Würzburg, Würzburg 97080, Germany [2] Rudolf Virchow Centre, University of Würzburg, Würzburg 97080, Germany.
authors.forename: Judith M M
authors.initials: JM
authors.lastname: van Eeuwijk
authors.affiliation: Department of Paediatrics and Adolescent Medicine, University Medical Centre Freiburg, Freiburg 79106, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Zieger
authors.affiliation: Department of Paediatrics, Jena University Hospital, Jena 07743, Germany.
authors.forename: Karim
authors.initials: K
authors.lastname: Kentouche
authors.affiliation: Department of Experimental Biomedicine, University Hospital, University of Würzburg, Würzburg 97080, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Schulze
authors.affiliation: Department of Pediatric Haematology, University Hospital Würzburg, Würzburg 97080, Germany.
authors.forename: Henner
authors.initials: H
authors.lastname: Morbach
authors.affiliation: 1] Department of Experimental Biomedicine, University Hospital, University of Würzburg, Würzburg 97080, Germany [2] Rudolf Virchow Centre, University of Würzburg, Würzburg 97080, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Stegner
authors.forename: Katrin G
authors.initials: KG
authors.lastname: Heinze
authors.affiliation: Rudolf Virchow Centre, University of Würzburg, Würzburg 97080, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Heinze
authors.affiliation: 1] Department of Experimental Biomedicine, University Hospital, University of Würzburg, Würzburg 97080, Germany [2] Rudolf Virchow Centre, University of Würzburg, Würzburg 97080, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Dütting
authors.affiliation: 1] Department of Experimental Biomedicine, University Hospital, University of Würzburg, Würzburg 97080, Germany [2] Rudolf Virchow Centre, University of Würzburg, Würzburg 97080, Germany.
authors.forename: Shuchi
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Institute of Genetics, University of Bonn, Bonn 53115, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Witke
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Hervé
authors.initials: H
authors.lastname: Falet
authors.affiliation: Unité d'Immunologie et d'Hématologie Pédiatrique, Hôpital Universitaire Necker-Enfants Malades, Paris 75015, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Hartwig
authors.affiliation: 1] Department of Experimental Biomedicine, University Hospital, University of Würzburg, Würzburg 97080, Germany [2] Rudolf Virchow Centre, University of Würzburg, Würzburg 97080, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
mesh_terms: D000293:Adolescent; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008870:Microtubules / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D051304:Profilins / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; C495739:Pfn1 protein, mouse; D051304:Profilins; C495767:WAS protein, human; C109903:WIPF1 protein, human; D051316:Wiskott-Aldrich Syndrome Protein