Redirecting differentiation of hematopoietic progenitors by a transcription factor, GATA-2

Kitajima, Kenji; Tanaka, Makoto; Zheng, Jie; Yen, Hilo; Sato, Ayuko; Sugiyama, Daijiro; Umehara, Hiroki; Sakai, Eiko; Nakano, Toru

doi:10.1182/blood-2005-06-2527

Cited by 71 publications

(60 citation statements)

References 52 publications

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“…A role for GATA-2 in inhibiting myelopoiesis is consistent with the ability of GATA-2 to physically interact with the Ets transcription factor PU.1 and interfere with its ability to transactivate target genes (60,63,64). This suggests that the inability of Notch signals to inhibit myelopoiesis from committed progenitors might be due to the high levels of PU.1 expressed by committed myeloid progenitors, which could preclude effective inhibition by GATA-2.…”

Section: Discussionmentioning

confidence: 60%

“…Alternatively, myeloid progenitors may no longer be responsive to Notch signals. Initially, GATA-2 does not appear to down-regulate the expression of PU.1, but rather to interfere with its function (64), although GATA-2 may inhibit PU.1 expression at later time points (60). This mechanism is consistent with our observation that PU.1 expression is equivalent between HPCs cultured on either OP9-control or OP9-DL1 cells, and with antagonism between PU.1 and another GATA family member, GATA-1, during erythropoiesis (64 -66, 67).…”

Section: Discussionmentioning

confidence: 99%

“…This avoided the inherent, confounding problems of forced overexpression of GATA-2 in hemopoiesis (59,60).…”

Section: Discussionmentioning

confidence: 99%

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Notch Signaling Requires GATA-2 to Inhibit Myelopoiesis from Embryonic Stem Cells and Primary Hemopoietic Progenitors

Pooter

Schmitt

Pompa

et al. 2006

The Journal of Immunology

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The bone marrow and thymus, although both hemopoietic environments, induce very distinct differentiation outcomes. The former supports hemopoietic stem cell self-renewal and multiple hemopoietic lineages, while the latter supports T lymphopoiesis almost exclusively. This distinction suggests that the thymic environment acts to restrict the hemopoietic fates available to thymic immigrants. In this study, we demonstrate that the addition of the Notch ligand Delta-like-1 (Dll-1) to an in vitro system that otherwise supports myelopoiesis, greatly reduces the myelopoietic potential of stem cells or uncommitted progenitors. In contrast, committed myeloid progenitors mature regardless of the presence of Dll-1. The block in myelopoiesis is the direct result of Notch signaling within the hemopoietic progenitor, and Dll-1-induced signals cause a rapid increase in the expression of the zinc finger transcription factor GATA-2. Importantly, in the absence of GATA-2, Dll-1-induced signals fail to inhibit commitment to the myeloid fate. Taken together, our results support a role for GATA-2 in allowing Dll-1 to restrict non-T cell lineage differentiation outcomes.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

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Notch Signaling Requires GATA-2 to Inhibit Myelopoiesis from Embryonic Stem Cells and Primary Hemopoietic Progenitors

Pooter

Schmitt

Pompa

et al. 2006

The Journal of Immunology

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“…Transcriptional regulation of PECAM-1 was documented to involve modulation of its gene promoter activity by the p65 subunit of NF-kB (52). The zinc finger transcription factor GATA-2 was initially shown to be crucial in modulating gene expression in megakaryocytic and erythroid lineages (53). Mounting evidence suggests that GATA-2 plays an important role in nonhematopoietic endothelial cells (54,55), where it is associated with PECAM-1 expression and participates in endothelial cell dedifferentiation (42,56).…”

Section: Discussionmentioning

confidence: 99%

Endothelial LSP1 Modulates Extravascular Neutrophil Chemotaxis by Regulating Nonhematopoietic Vascular PECAM-1 Expression

Hossain

Qadri

et al. 2015

The Journal of Immunology

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During inflammation, leukocyte–endothelial cell interactions generate molecular signals that regulate cell functions. The Ca2+- and F-actin–binding leukocyte-specific protein 1 (LSP1) expressed in leukocytes and nonhematopoietic endothelial cells is pivotal in regulating microvascular permeability and leukocyte recruitment. However, cell-specific function of LSP1 during leukocyte recruitment remains elusive. Using intravital microscopy of cremasteric microvasculature of chimeric LSP1-deficient mice, we show that not neutrophil but endothelial LSP1 regulates neutrophil transendothelial migration and extravascular directionality without affecting the speed of neutrophil migration in tissue in response to CXCL2 chemokine gradient. The expression of PECAM-1–sensitive α6β1 integrins on the surface of transmigrated neutrophils was blunted in mice deficient in endothelial LSP1. Functional blocking studies in vivo and in vitro elucidated that α6β1 integrins orchestrated extravascular directionality but not the speed of neutrophil migration. In LSP1-deficient mice, PECAM-1 expression was reduced in endothelial cells, but not in neutrophils. Similarly, LSP1-targeted small interfering RNA silencing in murine endothelial cells mitigated mRNA and protein expression of PECAM-1, but not ICAM-1 or VCAM-1. Overexpression of LSP1 in endothelial cells upregulated PECAM-1 expression. Furthermore, the expression of transcription factor GATA-2 that regulates endothelial PECAM-1 expression was blunted in LSP1-deficient or LSP1-silenced endothelial cells. The present study unravels endothelial LSP1 as a novel cell-specific regulator of integrin α6β1-dependent neutrophil extravascular chemotactic function in vivo, effective through GATA-2–dependent transcriptional regulation of endothelial PECAM-1 expression.

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“…GATA-2 is expressed abundantly in the mouse HSC population and is necessary for hematopoietic differentiation (Kitajima et al 2006). GATA-1 is expressed in megakaryocyte/erythrocyte precursors (MEP) and their progenitors, and GATA-3 is expressed in common lymphoid precursors (CLPs) and T cells.…”

Section: Irf-2 Interaction With Transcription Factors In Kslmentioning

confidence: 99%

Interferon Regulatory Factor-2 Regulates Hematopoietic Stem Cells in Mouse Bone Marrow

Masumi¹,

Miyatake²,

Kohno³

et al. 2012

Advances in Hematopoietic Stem Cell Research

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Redirecting differentiation of hematopoietic progenitors by a transcription factor, GATA-2

Cited by 71 publications

References 52 publications

Notch Signaling Requires GATA-2 to Inhibit Myelopoiesis from Embryonic Stem Cells and Primary Hemopoietic Progenitors

Notch Signaling Requires GATA-2 to Inhibit Myelopoiesis from Embryonic Stem Cells and Primary Hemopoietic Progenitors

Endothelial LSP1 Modulates Extravascular Neutrophil Chemotaxis by Regulating Nonhematopoietic Vascular PECAM-1 Expression

Interferon Regulatory Factor-2 Regulates Hematopoietic Stem Cells in Mouse Bone Marrow

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