Abnormal megakaryocyte development and platelet function in Nbeal2−/− mice

Kahr, Walter H.A.; Lo, Richard; Li, Ling; Pluthero, Fred G.; Christensen, Hilary; Ni, Ran; Vaezzadeh, Nima; Hawkins, Cynthia; Weyrich, Andrew S.; Paola, Jorge Di; Landolt-Marticorena, Carolina; Gross, Peter L.

doi:10.1182/blood-2013-04-499491

Cited by 103 publications

(126 citation statements)

References 38 publications

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“…1). Studies on various Nbeal2 knockout mouse models confirm that a-granules fail to form in MKs and/or be translocated into proplatelets and newly formed platelets [15][16][17]. These mouse models of GPS highlight how platelet a-granule proteins intervene in tissue repair, cause an inflammatory state in the marrow and contribute to thromboinflammatory states in the circulation (e.g., cerebral ischemia) and facilitate cancer metastasis thereby further raising interest in the disease.…”

Section: Gray Platelet Syndrome and The Nbeal2 Genementioning

confidence: 95%

Should any genetic defect affecting α‐granules in platelets be classified as gray platelet syndrome?

Nurden

2016

American J Hematol

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There is much current interest in the role of the platelet storage pool of α‐granule proteins both in hemostasis and non‐hemostatic events. As well as in the arrest of bleeding, the secreted proteins participate in wound healing, inflammation, and innate immunity while in pathology they may be actors in arterial thrombosis and atherosclerosis as well as cancer and metastasis. For a long time, gray platelet syndrome (GPS) has been regarded as the classic inherited platelet disorder caused by an absence of α‐granules and their contents. While NBEAL2 is the major source of mutations in GPS, other gene variants may give rise to significant α‐granule deficiencies in platelets. These include GATA1, VPS33B, or VIPAS39 in the arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome and now GFI1B. Nevertheless, many phenotypic differences are associated with mutations in these genes. This critical review was aimed to assess genotype/phenotype variability in disorders of platelet α‐granule biogenesis and to urge caution in grouping all genetic defects of α‐granules as GPS. Am. J. Hematol. 91:714–718, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Gray Platelet Syndrome and The Nbeal2 Genementioning

confidence: 95%

Should any genetic defect affecting α‐granules in platelets be classified as gray platelet syndrome?

Nurden

2016

American J Hematol

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“…28 Cells were pelleted by centrifugation, washed with PBS, and resuspended in PBS plus 1% BSA prior to spotting on coverslips (thickness No. 1.5) and incubation for 90 minutes at 37°C with saturating humidity.…”

Section: Laser Fluorescence Spinning Disk Confocal Microscopymentioning

confidence: 99%

“…Images were captured with a side-mounted high-resolution charge-coupled device camera (Advantage; Advanced Microscopy Techniques). 28 …”

Section: Transmission Electron Microscopymentioning

confidence: 99%

Dynamin 2–dependent endocytosis is required for normal megakaryocyte development in mice

Bender

Giannini

Grozovsky

et al. 2015

Blood

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Key Points• DNM2-dependent endocytosis in MKs regulates megakaryopoiesis, thrombopoiesis, and bone marrow homeostasis.Dynamins are highly conserved large GTPases (enzymes that hydrolyze guanosine triphosphate) involved in endocytosis and vesicle transport, and mutations in the ubiquitous and housekeeping dynamin 2 (DNM2) have been associated with thrombocytopenia in humans. To determine the role of DNM2 in thrombopoiesis, we generated Dnm2 fl/fl Pf4-Cre mice specifically lacking DNM2 in the megakaryocyte (MK) lineage. Dnm2fl/fl Pf4-Cre mice had severe macrothrombocytopenia with moderately accelerated platelet clearance. Dnm2-null bone marrow MKs had altered demarcation membrane system formation in vivo due to defective endocytic pathway, and fetal liver-derived Dnm2-null MKs formed proplatelets poorly in vitro, showing that DNM2-dependent endocytosis plays a major role in MK membrane formation and thrombopoiesis. Endocytosis of the thrombopoietin receptor Mpl was impaired in Dnm2-null platelets, causing constitutive phosphorylation of the tyrosine kinase JAK2 and elevated circulating thrombopoietin levels. MK-specific DNM2 deletion severely disrupted bone marrow homeostasis, as reflected by marked expansion of hematopoietic stem and progenitor cells, MK hyperplasia, myelofibrosis, and consequent extramedullary hematopoiesis and splenomegaly. Taken together, our data demonstrate that unrestrained MK growth and proliferation results in rapid myelofibrosis and establishes a previously unrecognized role for DNM2-dependent endocytosis in megakaryopoiesis, thrombopoiesis, and bone marrow homeostasis. (Blood. 2015;125(6):1014-1024

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“…Three mouse models with knockout of Nbeal2 have been generated recently. [104][105][106][107] While all three reproduce the macrothrombocytopenia and lack of α-granules in platelets, they display differences which are worth noting. The study from Kahr et al, 107 (Model 1), reports splenomegaly, like the human pathology, but no myelofibrosis.…”

Section: Gray Platelet Syndromementioning

confidence: 97%

“…[104][105][106][107] While all three reproduce the macrothrombocytopenia and lack of α-granules in platelets, they display differences which are worth noting. The study from Kahr et al, 107 (Model 1), reports splenomegaly, like the human pathology, but no myelofibrosis. Ultrastructural examination of megakaryocytes from these mice show abnormalities in the development of the DMS and in the maturation of α-granules, with an abundance of immature cells.…”

Section: Gray Platelet Syndromementioning

confidence: 97%

The contribution of mouse models to the understanding of constitutional thrombocytopenia

et al. 2016

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Article summary• Constitutional thrombocytopenias of hereditary origin have long been poorly studied due to the difficulties of obtaining invasive marrow samples.• Genetic engineering has allowed the generation of numerous mouse models for all these pathologies, providing invaluable information to understanding these diseases and serving as preclinical models to test new therapies.Constitutional thrombocytopenias result from genetic mutations affecting platelet production. These rare diseases are still underdiagnosed, especially in adults, because they remain little-known and have a highly variable expression. Autoimmune thrombocytopenia is still often wrongly diagnosed, thereby leading to the inadequate management of patients, with occasionally inappropriate splenectomy. The diagnosis of congenital thrombocytopenia relies on cytological and functional platelet analyses performed almost exclusively in specialized laboratories. Furthermore, about 50% of thrombocytopenias, associated or not with a thrombopathy, still remain of unknown origin. 1 In cases where platelet studies orient the diagnosis to a known disease, the detection of mutations in the suspected genes can C onstitutional thrombocytopenias result from platelet production abnormalities of hereditary origin. Long misdiagnosed and poorly studied, knowledge about these rare diseases has increased considerably over the last twenty years due to improved technology for the identification of mutations, as well as an improvement in obtaining megakaryocyte culture from patient hematopoietic stem cells. Simultaneously, the manipulation of mouse genes (transgenesis, total or conditional inactivation, introduction of point mutations, random chemical mutagenesis) have helped to generate disease models that have contributed greatly to deciphering patient clinical and laboratory features. Most of the thrombocytopenias for which the mutated genes have been identified now have a murine model counterpart. This review focuses on the contribution that these mouse models have brought to the understanding of hereditary thrombocytopenias with respect to what was known in humans. Animal models have either i) provided novel information on the molecular and cellular pathways that were missing from the patient studies; ii) improved our understanding of the mechanisms of thrombocytopoiesis; iii) been instrumental in structure-function studies of the mutated gene products; and iv) been an invaluable tool as preclinical models to test new drugs or develop gene therapies. At present, the genetic determinants of thrombocytopenia remain unknown in almost half of all cases. Currently available high-speed sequencing techniques will identify new candidate genes, which will in turn allow the generation of murine models to confirm and further study the abnormal phenotype. In a complementary manner, programs of random mutagenesis in mice should also identify new candidate genes involved in thrombocytopenia.The contribution of mouse models to the understanding of constitutional thrombocytope...

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Abnormal megakaryocyte development and platelet function in Nbeal2−/− mice

Cited by 103 publications

References 38 publications

Should any genetic defect affecting α‐granules in platelets be classified as gray platelet syndrome?

Should any genetic defect affecting α‐granules in platelets be classified as gray platelet syndrome?

Dynamin 2–dependent endocytosis is required for normal megakaryocyte development in mice

The contribution of mouse models to the understanding of constitutional thrombocytopenia

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