G6b-B regulates an essential step in megakaryocyte maturation
G6b-B regulates an essential step in megakaryocyte maturation
Abstract G6b-B is a megakaryocyte lineage-specific immunoreceptor tyrosine-based inhibition motif (ITIM)-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, while proplatelet release is hampered, but the underlying molecular mechanism remains unclear. Here, 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 in size, displayed a less developed demarcation membrane system and 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.
Englert Maximilian、Gross Carina、Bharti Richa、Mott Kristina、Heck Johannes、Schlegel Nicolas、Heckel Tobias、Haffner-Luntzer Melanie、Manukjan Georgi、Pleines Irina、Heib Tobias、Jeschke Anke、Nagy Zoltan、V?gtle Timo、Ignatius Anita、Schulze Harald、Dietrich Sascha、Stegner David、Nieswandt Bernhard、Schinke Thorsten、Becker Isabelle C.
Institute of Experimental Biomedicine, University Hospital, University of W¨1rzburg||Rudolf Virchow Center for Integrative and Translational Bioimaging, University of W¨1rzburgInstitute of Experimental Biomedicine, University Hospital, University of W¨1rzburg||Rudolf Virchow Center for Integrative and Translational Bioimaging, University of W¨1rzburgCore Unit Systems Medicine, University of W¨1rzburgInstitute of Experimental Biomedicine, University Hospital, University of W¨1rzburgInstitute of Experimental Biomedicine, University Hospital, University of W¨1rzburgDepartment of General Visceral, Vascular and Paediatric Surgery (Department of Surgery I), University of W¨1rzburgCore Unit Systems Medicine, University of W¨1rzburgInstitute of Orthopaedic Research and Biomechanics, University Medical Center UlmInstitute of Experimental Biomedicine, University Hospital, University of W¨1rzburgInstitute of Experimental Biomedicine, University Hospital, University of W¨1rzburg||Rudolf Virchow Center for Integrative and Translational Bioimaging, University of W¨1rzburgInstitute of Experimental Biomedicine, University Hospital, University of W¨1rzburg||Rudolf Virchow Center for Integrative and Translational Bioimaging, University of W¨1rzburgDepartment of Osteology and Biomechanics, University Medical Center Hamburg-EppendorfInstitute of Experimental Biomedicine, University Hospital, University of W¨1rzburg||Rudolf Virchow Center for Integrative and Translational Bioimaging, University of W¨1rzburgInstitute of Experimental Biomedicine, University Hospital, University of W¨1rzburg||Rudolf Virchow Center for Integrative and Translational Bioimaging, University of W¨1rzburgInstitute of Orthopaedic Research and Biomechanics, University Medical Center UlmInstitute of Experimental Biomedicine, University Hospital, University of W¨1rzburgCore Unit Systems Medicine, University of W¨1rzburgInstitute of Experimental Biomedicine, University Hospital, University of W¨1rzburg||Rudolf Virchow Center for Integrative and Translational Bioimaging, University of W¨1rzburgInstitute of Experimental Biomedicine, University Hospital, University of W¨1rzburg||Rudolf Virchow Center for Integrative and Translational Bioimaging, University of W¨1rzburgDepartment of Osteology and Biomechanics, University Medical Center Hamburg-EppendorfInstitute of Experimental Biomedicine, University Hospital, University of W¨1rzburg||Rudolf Virchow Center for Integrative and Translational Bioimaging, University of W¨1rzburg
基础医学分子生物学生理学
Englert Maximilian,Gross Carina,Bharti Richa,Mott Kristina,Heck Johannes,Schlegel Nicolas,Heckel Tobias,Haffner-Luntzer Melanie,Manukjan Georgi,Pleines Irina,Heib Tobias,Jeschke Anke,Nagy Zoltan,V?gtle Timo,Ignatius Anita,Schulze Harald,Dietrich Sascha,Stegner David,Nieswandt Bernhard,Schinke Thorsten,Becker Isabelle C..G6b-B regulates an essential step in megakaryocyte maturation[EB/OL].(2025-03-28)[2025-05-06].https://www.biorxiv.org/content/10.1101/2021.11.11.468226.点此复制
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