title: Mice lacking the ITIM-containing receptor G6b-B exhibit macrothrombocytopenia and aberrant platelet function.
abstract: Platelets are highly reactive cell fragments that adhere to exposed extracellular matrix (ECM) and prevent excessive blood loss by forming clots. Paradoxically, megakaryocytes, which produce platelets in the bone marrow, remain relatively refractory to the ECM-rich environment of the bone marrow despite having the same repertoire of receptors as platelets. These include the ITAM (immunoreceptor tyrosine-based activation motif)-containing collagen receptor complex, which consists of glycoprotein VI (GPVI) and the Fc receptor γ-chain, and the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing receptor G6b-B. We showed that mice lacking G6b-B exhibited macrothrombocytopenia (reduced platelet numbers and the presence of enlarged platelets) and a susceptibility to bleeding as a result of aberrant platelet production and function. Platelet numbers were markedly reduced in G6b-B-deficient mice compared to those in wild-type mice because of increased platelet turnover. Furthermore, megakaryocytes in G6b-B-deficient mice showed enhanced metalloproteinase production, which led to increased shedding of cell-surface receptors, including GPVI and GPIbα. In addition, G6b-B-deficient megakaryocytes exhibited reduced integrin-mediated functions and defective formation of proplatelets, the long filamentous projections from which platelets bud off. Together, these findings establish G6b-B as a major inhibitory receptor regulating megakaryocyte activation, function, and platelet production.
authors.affiliation: Centre of Cardiovascular Sciences, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Mazharian
authors.affiliation: Centre of Cardiovascular Sciences, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Centre of Cardiovascular Sciences, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Jun
authors.initials: J
authors.lastname: Mori
authors.affiliation: Centre of Cardiovascular Sciences, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Danai
authors.initials: D
authors.lastname: Bem
authors.affiliation: Centre of Cardiovascular Sciences, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Brenda
authors.initials: B
authors.lastname: Finney
authors.affiliation: Centre of Cardiovascular Sciences, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Silke
authors.initials: S
authors.lastname: Heising
authors.affiliation: Department of Medical and Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: White
authors.affiliation: Biomedical Diagnostics Institute, Dublin City University and Royal College of Surgeons in Ireland, Glasnevin, Dublin 9, Ireland.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Berndt
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Gardiner
authors.affiliation: University Hospital and Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Würzburg 97080, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.affiliation: Neuropharmacology and Neurobiology Section, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.|Department of Neurology, Dudley Group of Hospitals NHS Foundation Trust, Dudley DY1 2HQ, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Douglas
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Campbell
authors.affiliation: Centre of Cardiovascular Sciences, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
authors.affiliation: Centre of Cardiovascular Sciences, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Yotis A
authors.initials: YA
authors.lastname: Senis
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D048429:Cell Size; D008533:Megakaryocytes / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010976:Platelet Count; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C579533:G6b-B receptor, mouse; D008562:Membrane Glycoproteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D011971:Receptors, Immunologic; C094990:adhesion receptor; C098341:platelet membrane glycoprotein VI