Distinct, strict requirements for Gfi-1b in adult bone marrow red cell and platelet generation

Foudi, Adlen; Kramer, Daniel J.; Qin, Jinzhong; Ye, Denise; Behlich, Anna-Sophie; Mordecai, Scott; Preffer, Frederic I.; Amzallag, Arnaud; Ramaswamy, Sridhar; Hochedlinger, Konrad; Orkin, Stuart H.; Hock, Hanno

doi:10.1084/jem.20131065

Cited by 48 publications

(62 citation statements)

References 82 publications

(144 reference statements)

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“…GFI1B is a proto-oncogene and transcriptional regulator that with its paralog, GFI1, acts as a gene repressor during early hematopoietic stem cell development [22][23][24][25]. GFI1 primarily intervenes in myeloid and lymphoid generation and genetic variants cause neutropenia.…”

Section: Gfi1b Transcription Repressormentioning

confidence: 99%

“…As the patient with C168S also carried a a-actinin mutation, the latter would likely also contribute to the phenotype [30]. Significantly, Gfi1b knockout in mice is lethal and the MK and erythroid lineages fail to develop, while lack of Gfi1b in MKs in a conditional mouse model led to an arrest after nuclear polyploidization but before cytoplasmic maturation [24]. GFI1B can influence expression of surface adhesion molecules on blood cells and is a key element in the reciprocal regulation of blood cell lineages by regulator of G-protein signaling 18 (RGS18), a GTPase-activating protein that acts through mitogen-activated protein kinase family members [23,31].…”

Section: Gfi1b Transcription Repressormentioning

confidence: 99%

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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: Gfi1b Transcription Repressormentioning

confidence: 99%

Section: Gfi1b Transcription Repressormentioning

confidence: 99%

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

Nurden

2016

American J Hematol

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“…Growth factor independence 1b (Gfi1b) is a zinc-finger transcriptional repressor that is essential for the generation of the erythroid and megakaryocytic lineages (Foudi et al, 2014;Saleque et al, 2002), and is also required for lymphoid development (Doan et al, 2004;Schulz et al, 2012;van der Meer et al, 2010). Although Gfi1b is also moderately expressed in several other tissues, including non-hematopoietic ones (Tong et al, 1998;Vassen et al, 2007), the embryonic lethality resulting from the severe anemia following its germline deletion (Saleque et al, 2002) has, to date, precluded the analysis of its function in other developmental contexts.…”

Section: Introductionmentioning

confidence: 99%

Reciprocal regulation of alternative lineages by Rgs18 and its transcriptional repressor Gfi1b

Upadhyay

Sen

2016

Journal of Cell Science

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Appropriate diversification of cellular lineages from multi-potent progenitors is essential for normal development and homeostasis. The specification of erythroid and megakaryocytic lineages represents an especially vital developmental event whose molecular regulation remains incompletely defined. We now demonstrate the role of Rgs18, a GTPase-activating protein and transcriptional target of the repressor Gfi1b, in regulating these processes in mouse and human cells. Gfi1b stringently represses Rgs18 expression in erythroid cells, whereas, during megakaryocytic differentiation, declining Gfi1b levels facilitate a robust induction of Rgs18. Concordantly, alterations in Rgs18 expression produce disparate outcomes by augmenting megakaryocytic and potently suppressing erythroid differentiation and vice versa. These phenotypes reflect the differential impact of Rgs18 on signaling through p38 MAPK family proteins, and ERK1 and ERK2 (also known as MAPK3 and MAPK1, respectively) in the two lineages, which in turn alter the balance between the mutually antagonistic transcription factors Fli1 and Klf1. Overall, these results identify Rgs18 as a new and crucial effector of Gfi1b that regulates downstream signaling and gene expression programs to orchestrate erythro-megakaryocytic lineage choices. This dual role of Rgs18 in reciprocally regulating divergent lineages could exemplify generic mechanisms characteristic of multiple family members in different contexts.

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“…97 Finally, by crossing with mice expressing cre recombinase under the control of an inducible doxycycline promoter, it was possible to confirm the role of GFI1B as a transcriptional repressor of adult erythropoiesis and thrombopoiesis. 98 During megakaryopoiesis in adults, GFI1B acts as a repressor mainly after the completion of endomitoses but before the onset of cytoplasmic maturation.…”

Section: Thrombocytopenia Associated With Gfi1bmentioning

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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Distinct, strict requirements for Gfi-1b in adult bone marrow red cell and platelet generation

Abstract: Strict, lineage-intrinsic requirement for continuous adult Gfi-1b expression at two distinct critical stages of erythropoiesis and megakaryopoiesis.

Cited by 48 publications

References 82 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?

Reciprocal regulation of alternative lineages by Rgs18 and its transcriptional repressor Gfi1b

The contribution of mouse models to the understanding of constitutional thrombocytopenia

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