G6b-B regulates an essential step in megakaryocyte maturation

TY - JOUR

T1 - G6b-B regulates an essential step in megakaryocyte maturation

AU - Becker, Isabelle C

AU - Nagy, Zoltan

AU - Manukjan, Georgi

AU - Haffner-Luntzer, Melanie

AU - Englert, Maximilian

AU - Heib, Tobias

AU - Vögtle, Timo

AU - Gross, Carina

AU - Bharti, Richa

AU - Dietrich, Sascha

AU - Mott, Kristina

AU - Heck, Johannes

AU - Stegmaier, Sebastian

AU - Baranowsky, Anke

AU - Schinke, Thorsten

AU - Schlegel, Nicolas

AU - Heckel, Tobias

AU - Stegner, David

AU - Pleines, Irina

AU - Ignatius, Anita

AU - Schulze, Harald

AU - Nieswandt, Bernhard

N1 - Copyright © 2022 American Society of Hematology.

PY - 2022/5/24

Y1 - 2022/5/24

N2 - 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.

AB - 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.

U2 - 10.1182/bloodadvances.2021006151

DO - 10.1182/bloodadvances.2021006151

M3 - SCORING: Journal article

C2 - 35134123

VL - 6

SP - 3155

EP - 3161

JO - BLOOD ADV

JF - BLOOD ADV

SN - 2473-9529

IS - 10

ER -