G6b-B regulates an essential step in megakaryocyte maturation

Autor: Isabelle C. Becker, Zoltan Nagy, Georgi Manukjan, Melanie Haffner-Luntzer, Maximilian Englert, Tobias Heib, Timo Vögtle, Carina Gross, Richa Bharti, Sascha Dietrich, Kristina Mott, Johannes Heck, Sebastian Stegmaier, Anke Baranowsky, Thorsten Schinke, Nicolas Schlegel, Tobias Heckel, David Stegner, Irina Pleines, Anita Ignatius, Harald Schulze, Bernhard Nieswandt
Rok vydání: 2022
Předmět:
Zdroj: Blood Advances. 6:3155-3161
ISSN: 2473-9537
2473-9529
Popis: 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.
Databáze: OpenAIRE
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