G6b-B regulates an essential step in megakaryocyte maturation
Cold Spring Harbor Laboratory, 2021
Online
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Zugriff:
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.
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G6b-B regulates an essential step in megakaryocyte maturation
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Autor/in / Beteiligte Person: | Schulze, Harald ; Heck, J. ; Heib, T. ; Bharti, R. ; Haffner-Luntzer, M. ; Nieswandt, Bernhard ; Ignatius, A. ; Manukjan, Georgi ; Englert, M. ; Dietrich, S. ; Mott, K. ; Becker, I. C. ; Pleines, Irina ; Schlegel, N. ; Schinke, T. ; Heckel, T. ; Jeschke, A. ; Nagy, Zoltan ; Gross, C. ; Voegtle, T. ; Stegner, David |
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Veröffentlichung: | Cold Spring Harbor Laboratory, 2021 |
Medientyp: | unknown |
DOI: | 10.1101/2021.11.11.468226 |
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