title: Gfi1bcontrols integrin signaling-dependent cytoskeleton dynamics and organization in megakaryocytes.
abstract: Mutations inGFI1Bare associated with inherited bleeding disorders calledGFI1B-related thrombocytopenias. We show here that mice with a megakaryocyte-specificGfi1bdeletion exhibit a macrothrombocytopenic phenotype along a megakaryocytic dysplasia reminiscent ofGFI1B-related thrombocytopenia. GFI1B deficiency increases megakaryocyte proliferation and affects their ploidy, but also abrogates their responsiveness towards integrin signaling and their ability to spread and reorganize their cytoskeleton.Gfi1b-null megakaryocytes are also unable to form proplatelets, a process independent of integrin signaling. GFI1B-deficient megakaryocytes exhibit aberrant expression of several components of both the actin and microtubule cytoskeleton, with a dramatic reduction of α-tubulin. Inhibition of FAK or ROCK, both important for actin cytoskeleton organization and integrin signaling, only partially restored their response to integrin ligands, but the inhibition of PAK, a regulator of the actin cytoskeleton, completely rescued the responsiveness ofGfi1b-null megakaryocytes to ligands, but not their ability to form proplatelets. We conclude thatGfi1bcontrols major functions of megakaryocytes such as integrin-dependent cytoskeleton organization, spreading and migration through the regulation of PAK activity whereas the proplatelet formation defect in GFI1B-deficient megakaryocytes is due, at least partially, to an insufficient α-tubulin content.
authors.affiliation: Institut de Recherches Cliniques de Montréal, IRCM, QC, Canada.
authors.forename: Hugues
authors.initials: H
authors.lastname: Beauchemin
authors.affiliation: Institut de Recherches Cliniques de Montréal, IRCM, QC, Canada.
authors.forename: Peiman
authors.initials: P
authors.lastname: Shooshtarizadeh
authors.affiliation: Institut de Recherches Cliniques de Montréal, IRCM, QC, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Vadnais
authors.affiliation: Institut de Recherches Cliniques de Montréal, IRCM, QC, Canada.
authors.forename: Lothar
authors.initials: L
authors.lastname: Vassen
authors.affiliation: Département de Pédiatrie, Service d'Hématologie et Oncologie, CHU Ste-Justine, Montréal, QC, Canada.
authors.forename: Yves D
authors.initials: YD
authors.lastname: Pastore
authors.affiliation: Institut de Recherches Cliniques de Montréal, IRCM, QC, Canada tarik.moroy@ircm.qc.ca.|Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, QC, Canada.|Division of Experimental Medicine, McGill University, Montréal, QC, Canada.
authors.forename: Tarik
authors.initials: T
authors.lastname: Möröy
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism*; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D016023:Integrins / Q000378:metabolism*; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism; D010641:Phenotype; D010976:Platelet Count; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055503:Protein Multimerization; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D013921:Thrombocytopenia / Q000097:blood / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D000199:Actins; C486395:Gfi1b protein, mouse; D016023:Integrins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins