Genetic deletion of mouse platelet glycoprotein Ibβ produces a Bernard-Soulier phenotype with increased α-granule size

Kato, Kazunobu; Martínez, Constantino; Russell, Susan; Nurden, Paquita; Nurden, Alan T.; Fiering, Steven; Ware, Jerry

doi:10.1182/blood-2004-03-1127

Cited by 89 publications

(69 citation statements)

References 33 publications

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“…This contrasted with the report of α-granules of increased size in another GPIbβ -/-strain 49 which was attributed to up-reg-ulation of SEPT5 expression whose gene is located 5' to the GPIBB gene and modulates exocytosis. This discrepancy is difficult to explain but does not appear to be due to the targeting strategy which was very similar in the two studies with insertion of a neo cassette at the same 5'-restriction site, and only differed in the length of the 3' untranslated region .…”

Section: Discussioncontrasting

confidence: 54%

“…52 These results provide a good indication that the mouse model properly reproduces the defects in the human disease. Therefore, available GPIbβ-and by extension GPIbα-deficient mice 27,49,53 represent appropriate models to pursue studies of the role of GPIb-V-IX in thrombopoiesis. Use of such models in rescue studies with selected mutagenesis of the receptor should increase our knowledge of the mechanisms of megakaryocyte maturation and platelet formation.…”

Section: Discussionmentioning

confidence: 99%

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Intrinsic impaired proplatelet formation and microtubule coil assembly of megakaryocytes in a mouse model of Bernard-Soulier syndrome

Strassel¹,

Eckly²,

Léon³

et al. 2009

Haematologica

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The online version of this article contains a supplementary appendix. BackgroundGiant platelets and thrombocytopenia are invariable defects in the Bernard-Soulier syndrome caused by deficiency of the GPIb-V-IX complex, a receptor for von Willebrand factor supporting platelet adhesion to the damaged arterial wall. Various properties of this receptor may be considered potential determinants of the macrothrombocytopenia. Design and MethodsTo explore the underlying mechanisms of the disease, megakaryopoiesis was studied in a mouse model deficient in GPIbβ. Megakaryocytes were initially characterized in situ in the bone marrow of adult mice, after which their capacity to differentiate into proplateletbearing cells was evaluated in cultured fetal liver cells. ResultsThe number of megakaryocyte progenitors, their differentiation and progressive maturation into distinct classes and their level of endoreplication were normal in GPIbβ -/-bone marrow. However, the more mature cells exhibited ultrastructural anomalies with a thicker peripheral zone and a less well developed demarcation membrane system. GPIbβ -/-megakaryocytes could be differentiated in culture from Lin -fetal liver cells in normal amounts but the proportion of cells able to extend proplatelets was decreased by 41%. Moreover, the GPIbβ -/-cells extending proplatelets displayed an abnormal morphology characterized by fewer pseudopodial extensions with thicker shaft sections and an increased diameter of the terminal coiled elements. GPIbβ -/-released platelets were larger but retained a typical discoid shape. Proplatelet formation was similarly affected in bone marrow explants from adult mice examined by videomicroscopy. The marginal microtubular ring contained twice as many tubulin fibers in GPIbβ -/-proplatelet buds in cultured and circulating platelets. ConclusionsAltogether, these findings point to a role of the GPIb-V-IX complex intrinsic to megakaryocytes at the stage of proplatelet formation and suggest a functional link with the underlying microtubular cytoskeleton in platelet biogenesis.Key words: megakaryocyte, platelet, Bernar-Soulier, microtubules, GPIb-V-IX.Citation: Strassel C, Eckly A, Léon C, Petitjean C, Freund M, Cazenave J-P, Gachet C, and Lanza F. Intrinsic impaired proplatelet formation and microtubule coil assembly of megakaryocytes in a mouse model of Bernard-Soulier syndrome. Haematologica 2009; 94:800-810. doi:10.3324/haematol.2008 This is an open-access paper.

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Section: Discussioncontrasting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Intrinsic impaired proplatelet formation and microtubule coil assembly of megakaryocytes in a mouse model of Bernard-Soulier syndrome

Strassel¹,

Eckly²,

Léon³

et al. 2009

Haematologica

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“…However, the interpretation of this latter finding is complicated by the juxtaposition of the platelet glycoprotein 1b gene and the Sept5 gene in mouse and man. Indeed, some SEPT5 transcripts use 3 sequences from the glycoprotein 1b gene [131], so it may be that the platelet phenotype of the Sept5 knock-out mice is a serendipitous artefact of the targeting strategy employed.…”

Section: Septins Vesicle Trafficking and Membrane Eventsmentioning

confidence: 99%

The pathobiology of the septin gene family

Hall

Russell

2004

The Journal of Pathology

288

283

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Septins are an evolutionarily conserved group of GTP-binding and filament-forming proteins that belong to the large superclass of P-loop GTPases. While originally discovered in yeast as cell division cycle mutants with cytokinesis defects, they are now known to have diverse cellular roles which include polarity determination, cytoskeletal reorganization, membrane dynamics, vesicle trafficking, and exocytosis. Septin proteins form homo-and heterooligomeric polymers which can assemble into higher-order filaments. They are also known to interact with components of the cytoskeleton, ie actin and tubulin. The precise role of GTP binding is not clear but a current model suggests that it is associated with conformational changes which alter binding to other proteins. There are at least 12 human septin genes, and although information on expression patterns is limited, most undergo complex alternative splicing with some degree of tissue specificity. Nevertheless, an increasing body of data implicates the septin family in the pathogenesis of diverse disease states including neoplasia, neurodegenerative conditions, and infections. Here the known biochemical properties of mammalian septins are reviewed in the light of the data from yeast and other model organisms. The data implicating septins in human disease are considered and a model linking these data is proposed. It is posited that septins can act as regulatable scaffolds where the stoichiometry of septin associations, modifications, GTP status, and the interactions with other proteins allow the regulation of key cellular processes including polarity determination. Derangements of such septin scaffolds thus explain the role of septins in disease states.

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“…Various BSS mouse models have been developed and have helped to explore potential mechanisms involving cytoskeletal proteins. Among these models, complete inactivation of the gene encoding GPIbα 23 or GPIbβ 24,25 reproduces the bleeding phenotype, macrothrombocytopenia and failure to extend proplatelets. The decrease in proplatelet formation may partly result from a lack of maturation of megakaryocytes, as shown especially by abnormalities in the development of the DMS observed in situ.…”

Section: Bernard-soulier Syndromementioning

confidence: 99%

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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Genetic deletion of mouse platelet glycoprotein Ibβ produces a Bernard-Soulier phenotype with increased α-granule size

Cited by 89 publications

References 33 publications

Intrinsic impaired proplatelet formation and microtubule coil assembly of megakaryocytes in a mouse model of Bernard-Soulier syndrome

Intrinsic impaired proplatelet formation and microtubule coil assembly of megakaryocytes in a mouse model of Bernard-Soulier syndrome

The pathobiology of the septin gene family

The contribution of mouse models to the understanding of constitutional thrombocytopenia

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