Mice Lacking the ITIM-Containing Receptor G6b-B Exhibit Macrothrombocytopenia and Aberrant Platelet Function

Mazharian, Alexandra; Wang, Ying Jie; Mori, Jun; Bem, Danai; Finney, Brenda; Heising, Silke; Gissen, Paul; White, James G.; Berndt, Michael C.; Gardiner, Elizabeth E.; Nieswandt, Bernhard; Douglas, Michael E.; Campbell, R D; Watson, Steve P.; Senis, Yotis A.

doi:10.1126/scisignal.2002936

Cited by 71 publications

(176 citation statements)

References 68 publications

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“…The cause of enhanced reactivity of Shp2-deficient platelets to fibrinogen remains undefined; however, enhanced reactivity to anti-CLEC-2 antibody likely involves G6b-B. 19 Functional differences exhibited by Shp1-and Shp2-deficient megakaryocytes highlight the different roles mediated by Shp1 and Shp2. The only overlapping phenotype was the block in 2N/4N ploidy and reduced aIIbb3 surface expression, which likely reflects less mature megakaryocytes.…”

Section: Discussionmentioning

confidence: 99%

“…We focused on the ITIM-containing receptor G6b-B that is highly expressed in mature megakaryocytes and platelets (supplemental Figures 2A and 8A) 20,46 and is constitutively tyrosine phosphorylated and associated with Shp1 and Shp2. 19 This suggests that G6b-B anchors active Shp1 and Shp2 at the plasma membrane (supplemental Figure 1C). To determine whether G6b-B lies upstream of Shp1 and Shp2, we compared the phenotypes of MP-specific G6b conditional KO mice (MP-G6b KO) with MP-Shp1 and MPShp2 KO mice.…”

Section: Reduced Tpo and Integrin Signaling In Shp2-deficient Megakarmentioning

confidence: 99%

“…[11][12][13][14] Five ITIM-containing receptors have been identified in megakaryocytes and/or platelets to date, namely PECAM-1, carcinoembryonic antigen-related cell adhesion molecule 1, TREM-like transcript-1, leukocyte-associated immunoglobulin-like receptor-1, and G6b-B, all of which interact with Shp1 and Shp2 upon phosphorylation. [15][16][17][18][19] Unique among these is G6b-B, which is constitutively phosphorylated by SFKs and associated with Shp1 and Shp2 (supplemental Figure 1C). 20,21 Thus, G6b-B is thought to maintain active Shp1 and Shp2 at the plasma membrane, where they inhibit signaling from various receptors.…”

Section: Introductionmentioning

confidence: 99%

“…26,27 Targeted deletion of G6b causes severe macrothrombocytopenia and a bleeding diathesis due to enhanced platelet clearance, and aberrant platelet production and function. 19 In this study, we investigated the functions of Shp1 and Shp2 in megakaryocytes and platelets through the use of megakaryocyte/ platelet (MP)-specific Ptpn6 and Ptpn11 single and double conditional knockout (KO) mouse models. The distinct phenotypes exhibited by the Shp1 and Shp2 conditional KO mice highlight the disparate physiological functions of these structurally related PTPs in megakaryocytes and platelets.…”

Section: Introductionmentioning

confidence: 99%

“…, and PF4-Cre 1 mice were generated, as previously described. 19,28-30 MP-specific Shp1, Shp2, and G6b KO mice were generated by crossing Ptpn6 …”

Section: Introductionmentioning

confidence: 99%

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Megakaryocyte-specific deletion of the protein-tyrosine phosphatases Shp1 and Shp2 causes abnormal megakaryocyte development, platelet production, and function

Mazharian

Mori

Wang

et al. 2013

Blood

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Key Points• The protein-tyrosine phosphatases Shp1 and Shp2 are critical regulators of megakaryocyte development, platelet production, and function.• Shp1 and Shp2 perform mainly distinct functions in megakaryocytes and platelets, with little functional overlap.The SH2 domain-containing protein-tyrosine phosphatases Shp1 and Shp2 have been implicated in regulating signaling from a variety of platelet and megakaryocyte receptors.In this study, we investigate the functions of Shp1 and Shp2 in megakaryocytes and platelets. Megakaryocyte/platelet (MP)-specific deletion of Shp1 in mice resulted in platelets being less responsive to collagen-related peptide due to reduced GPVI expression and signaling via the Src family kinase (SFK)-Syk-PLCg2 pathway, and fibrinogen due to reduced SFK activity. By contrast, deletion of Shp2 in the MP lineage resulted in macrothrombocytopenia and platelets being hyper-responsive to anti-CLEC-2 antibody and fibrinogen. Shp1-and Shp2-deficient megakaryocytes had partial blocks at 2N/4N ploidy; however, only the latter exhibited reduced proplatelet formation, thrombopoietin, and integrin signaling. Mice deficient in both Shp1 and Shp2 were severely macrothrombocytopenic and had reduced platelet surface glycoprotein expression, including GPVI, aIIbb3, and GPIba. Megakaryocytes from these mice were blocked at 2N/4N ploidy and did not survive ex vivo. Deletion of the immunoreceptor tyrosine-based inhibition motif-containing receptor G6b-B in the MP lineage phenocopied multiple features of Shp1/2-deficient mice, suggesting G6b-B is a critical regulator of Shp1 and Shp2. This study establishes Shp1 and Shp2 as major regulators of megakaryocyte development, platelet production, and function. (Blood. 2013;121(20):4205-4220)

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Section: Discussionmentioning

confidence: 99%

Section: Reduced Tpo and Integrin Signaling In Shp2-deficient Megakarmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…, and PF4-Cre 1 mice were generated, as previously described. 19,28-30 MP-specific Shp1, Shp2, and G6b KO mice were generated by crossing Ptpn6 …”

Section: Introductionmentioning

confidence: 99%

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Megakaryocyte-specific deletion of the protein-tyrosine phosphatases Shp1 and Shp2 causes abnormal megakaryocyte development, platelet production, and function

Mazharian

Mori

Wang

et al. 2013

Blood

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Severity of Megakaryocyte-Driven Osteosclerosis in Mpig6b-Deficient Mice Is Sex-Linked

Stavnichuk

Tauer

Nagy

et al. 2020

Journal of Bone and Mineral Research

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Patients with chronic myelofibrosis often suffer from osteosclerosis, which is associated with bone pain and may lead to bone marrow failure. The pathogenesis of myelofibrosis is linked to aberrant megakaryocyte development and function. Null and loss‐of‐function mutations in MPIG6B, which codes for the inhibitory heparan sulfate receptor G6b‐B, result in severe macrothrombocytopenia, large megakaryocyte clusters, and focal primary myelofibrosis in mice and humans. We investigated the development of osteosclerosis in Mpig6b null (Mpig6b−/−) mice. Although male and female Mpig6b−/− mice presented with elevated bone marrow megakaryocyte number and macrothrombocytopenia, female Mpig6b−/− mice developed progressive splenomegaly starting at 8 weeks of age. Micro–computed tomography (μCT) of femurs showed that female Mpig6b−/− mice had increased cortical thickness and reduced bone marrow area starting at 8 weeks of age and developed occlusion of the medullary cavity by trabeculae by 16 weeks of age. In contrast, male Mpig6b−/− mice developed only a small number of trabeculae in the medullary cavity at the proximal diaphysis and demonstrated a temporary decrease in bone volume fraction and trabecular thickness at 16 weeks. Ovariectomy of 10‐week‐old female Mpig6b−/− mice prevented the development of medullary cavity osteosclerosis, whereas orchiectomy of male Mpig6b−/− mice did not exacerbate their disease. Importantly, ovariectomized female Mpig6b−/− mice also demonstrated improvement in spleen weight compared to sham‐operated Mpig6b−/− mice, establishing estrogen as a contributing factor to the severity of the megakaryocyte‐driven osteosclerosis. © 2021 American Society for Bone and Mineral Research (ASBMR).

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Detrimental variants in MPIG6B in two children with myelofibrosis: Does immune dysregulation contribute to myelofibrosis?

Batis

Almugairi

Almugren

et al. 2021

Pediatric Blood & Cancer

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is a rare disorder in children. It mostly occurs secondary to disorders such as malignancy, vitamin D deficiency, autoimmunity, and infections. 1,2 Primary MF has been reported in a limited number of children. [3][4][5] Germline mutations in genes such as MPL, VPS45, and RBSN are associated with primary MF. 6-8 A recent report described an Arab family with MF associated with a homozygous mutation in MPIG6B (also known as G6B or C6orf25). 9Another report described four unrelated Arab families with homozygous loss-of-function variants in MPIG6B associated with childhood MF. 10 MPIG6B is located in the class III region of the major histocompatibility complex and encodes G6B protein that interacts with protein tyrosine phosphatases Shp1 and Shp2. 11,12 G6B is primarily expressed in platelets. [13][14][15] G6B knockout mice had low platelet count, increased platelet volume, and platelet dysfunction. 10,16 We report two unrelated patients who presented during infancy with anemia, thrombocytopenia, and focal MF and had homozygous mutations in MPIG6B. The first case is a 10-year-old female who presented at 7 months of age with epistaxis and had thrombocytopenia and anemia. Her parents are first cousins. Physical examination was unremarkable. Blood smear showed some giant platelets and anisopoikilocytosis with teardrop cells, schistocytes, elliptocytes, and spherocytes. Bone marrow (BM) at age 1 year was hypercellular with megakaryocyte clusters, as shown in Figure S1. BM was infiltrated with large cells with vesicular nuclei and prominent nucleoli and was surrounded by a mixture of small lymphocytes and eosinophils.The large cells were positive for CD10, CD20, CD45, and CD79a and negative for CD3, CD7, CD15, CD30, CD34, CD56, CD57, pan CK, desmin, and synaptophysin. The background cells were positive for CD15, CD45, MPO and negative for other markers. There was a mild increase in reticulin fibers. Follow-up BM studies showed subsequent fading of lymphocytic infiltration, dysplastic megakaryocytes, a slight reduction in erythropoiesis, and a marked increase in MF with no myelodysplasia (Figure S1). Cytogenetic analysis was normal.Chromosomal fragility test, vitamin D, vitamin B12, and folate levels were normal. The patient required intermittent platelet transfusion.There was no major bleeding. The spleen progressively increased in size with an increase in platelet transfusion requirements. Splenectomy led to transient improvement in platelet counts. Whole exome sequencing (WES) revealed a homozygous loss-of-function mutation in MPIG6B: c.523C>T (p.Arg175Ter). Recently, the patient started to

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Mice Lacking the ITIM-Containing Receptor G6b-B Exhibit Macrothrombocytopenia and Aberrant Platelet Function

Cited by 71 publications

References 68 publications

Megakaryocyte-specific deletion of the protein-tyrosine phosphatases Shp1 and Shp2 causes abnormal megakaryocyte development, platelet production, and function

Megakaryocyte-specific deletion of the protein-tyrosine phosphatases Shp1 and Shp2 causes abnormal megakaryocyte development, platelet production, and function

Severity of Megakaryocyte-Driven Osteosclerosis in Mpig6b-Deficient Mice Is Sex-Linked

Detrimental variants in MPIG6B in two children with myelofibrosis: Does immune dysregulation contribute to myelofibrosis?

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