Mice Lacking the ITIM-Containing Receptor G6b-B Exhibit Macrothrombocytopenia and Aberrant Platelet Function

Sci. Signal., 30 October 2012
Vol. 5, Issue 248, p. ra78
DOI: 10.1126/scisignal.2002936

Mice Lacking the ITIM-Containing Receptor G6b-B Exhibit Macrothrombocytopenia and Aberrant Platelet Function

  1. Alexandra Mazharian1,*,
  2. Ying-Jie Wang1,*,,
  3. Jun Mori1,
  4. Danai Bem1,
  5. Brenda Finney1,
  6. Silke Heising1,
  7. Paul Gissen2,,
  8. James G. White3,
  9. Michael C. Berndt4,
  10. Elizabeth E. Gardiner5,
  11. Bernhard Nieswandt6,
  12. Michael R. Douglas7,8,
  13. Robert D. Campbell9,
  14. Steve P. Watson1, and
  15. Yotis A. Senis1,§
  1. 1Centre 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.
  2. 2Department of Medical and Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
  3. 3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
  4. 4Biomedical Diagnostics Institute, Dublin City University and Royal College of Surgeons in Ireland, Glasnevin, Dublin 9, Ireland.
  5. 5Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia.
  6. 6University Hospital and Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Würzburg 97080, Germany.
  7. 7Neuropharmacology and Neurobiology Section, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
  8. 8Department of Neurology, Dudley Group of Hospitals NHS Foundation Trust, Dudley DY1 2HQ, UK.
  9. 9Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
  1. §To whom correspondence should be addressed. E-mail: y.senis{at}bham.ac.uk
  • * These authors contributed equally to this work.

  • Present address: Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.

  • Present address: Medical Research Council Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, UK.

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.

Citation:

A. Mazharian, Y.-J. Wang, J. Mori, D. Bem, B. Finney, S. Heising, P. Gissen, J. G. White, M. C. Berndt, E. E. Gardiner, B. Nieswandt, M. R. Douglas, R. D. Campbell, S. P. Watson, and Y. A. Senis, Mice Lacking the ITIM-Containing Receptor G6b-B Exhibit Macrothrombocytopenia and Aberrant Platelet Function. Sci. Signal. 5, ra78 (2012).

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