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Becker, Isabelle C.; Nagy, Zoltan; Manukjan, Georgi; Haffner-Luntzer, Melanie; Englert, Maximilian; Heib, Tobias; Vögtle, Timo; Gross, Carina; Bharti, Richa; Dietrich, Sascha; Mott, Kristina; Heck, Johannes; Stegmaier, Sebastian; Baranowsky, Anke; Schinke, Thorsten; Schlegel, Nicolas; Heckel, Tobias; Stegner, David; Pleines, Irina; Ignatius, Anita; Schulze, Harald; Nieswandt, Bernhard

G6b-B regulates an essential step in megakaryocyte maturation

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  • Medientyp: E-Artikel
  • Titel: G6b-B regulates an essential step in megakaryocyte maturation
  • Beteiligte: Becker, Isabelle C.; Nagy, Zoltan; Manukjan, Georgi; Haffner-Luntzer, Melanie; Englert, Maximilian; Heib, Tobias; Vögtle, Timo; Gross, Carina; Bharti, Richa; Dietrich, Sascha; Mott, Kristina; Heck, Johannes; Stegmaier, Sebastian; Baranowsky, Anke; Schinke, Thorsten; Schlegel, Nicolas; Heckel, Tobias; Stegner, David; Pleines, Irina; Ignatius, Anita; Schulze, Harald; Nieswandt, Bernhard
  • Erschienen: American Society of Hematology, 2022
  • Erschienen in: Blood Advances, 6 (2022) 10, Seite 3155-3161
  • Sprache: Englisch
  • DOI: 10.1182/bloodadvances.2021006151
  • ISSN: 2473-9529; 2473-9537
  • Entstehung:
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  • Beschreibung: Abstract G6b-B is a megakaryocyte lineage-specific immunoreceptor tyrosine-based inhibition motif–containing receptor, essential for platelet homeostasis. Mice with a genomic deletion of the entire Mpig6b locus develop severe macrothrombocytopenia and myelofibrosis, which is reflected in humans with null mutations in MPIG6B. The current model proposes that megakaryocytes lacking G6b-B develop normally, whereas proplatelet release is hampered, but the underlying molecular mechanism remains unclear. We report on a spontaneous recessive single nucleotide mutation in C57BL/6 mice, localized within the intronic region of the Mpig6b locus that abolishes G6b-B expression and reproduces macrothrombocytopenia, myelofibrosis, and osteosclerosis. As the mutation is based on a single-nucleotide exchange, Mpig6bmut mice represent an ideal model to study the role of G6b-B. Megakaryocytes from these mice were smaller, displayed a less-developed demarcation membrane system, and had a reduced expression of receptors. RNA sequencing revealed a striking global reduction in the level of megakaryocyte-specific transcripts, in conjunction with decreased protein levels of the transcription factor GATA-1 and impaired thrombopoietin signaling. The reduced number of mature MKs in the bone marrow was corroborated on a newly developed Mpig6b-null mouse strain. Our findings highlight an unexpected essential role of G6b-B in the early differentiation within the megakaryocytic lineage.
  • Zugangsstatus: Freier Zugang