AML1/Runx1 rescues Notch1-null mutation-induced deficiency of para-aortic splanchnopleural hematopoiesis

Nakagawa, Masahiro; Ichikawa, Motoshi; Kumano, Keiki; Goyama, Susumu; Kawazu, Masahito; Asai, Takashi; Ogawa, Seishi; Kurokawa, Mineo; Chiba, Shigeru

doi:10.1182/blood-2006-04-019570

Cited by 84 publications

(71 citation statements)

References 32 publications

(42 reference statements)

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“…Runx1 has been recently described to act downstream of Notch in the establishment of the hematopoietic stem cell fate in the zebrafish embryo (Burns et al, 2005). In addition, ectopic expression of runx1 (but not gata2 or scl) partially rescues the hematopoietic defects of Notch1 -/-AGM-derived cells in vitro (Nakagawa et al, 2006). Although there is no evidence for a direct effect of Notch on the runx1 gene (Robert-Moreno et al, 2005), it is possible that Notch regulates runx1 downstream of gata2 (Nottingham et al, 2007).…”

Section: Notch Target Genesmentioning

confidence: 90%

The Notch pathway in the developing hematopoietic system

Bigas

Robert‐Moreno²,

Espinosa³

2010

Int. J. Dev. Biol.

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The main function of the Notch signaling pathway is to generate cell diversity during both embryonic development and adult tissue homeostasis. The extended use of this pathway, together with its conservation during evolution, is indicative of its importance. During embryonic development, the vascular and hematopoietic systems are intimately associated and Notch signals are responsible for the correct specification of both systems. More explicitly, Notch is required for the induction of the arterial program; however, it is simultaneously or consecutively also involved in the generation of hematopoietic stem cells. Although both genetic programs are different, they are both implemented in endothelial cells of the dorsal aorta in the midgestation embryo. This close association during the development of arteries and blood has hindered our understanding of Notch function in the generation of hematopoietic stem cells. Here, we will review the work from recent years showing how Notch participates in the embryonic development of hematopoiesis in the mouse, but also in other organisms such as chick, zebrafish and flies.

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Section: Notch Target Genesmentioning

confidence: 90%

The Notch pathway in the developing hematopoietic system

Bigas

Robert‐Moreno²,

Espinosa³

2010

Int. J. Dev. Biol.

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“…However, deficiency of these genes does not completely recapitulate the phenotype of targeting Notch or CSL in the heart (31,36), suggesting that these target genes mediate only a subset of functions of Notch. RUNX1 is shown to be a critical downstream effector of Notch in hematopoiesis (20,27), and RUNX3 is induced by Notch during human T-cell development (37), suggesting a potential role of RUNX proteins in Notch signaling. Here, we report that RUNX3, but not RUNX1, is the major RUNX protein to be induced by Notch in endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…functional Notch-RUNX axis has been suggested in hematopoiesis in zebrafish and mouse (20,27). To investigate whether RUNX proteins are downstream targets of Notch in endothelial cells, we activated Notch signaling in HMEC by overexpression of constitutively-active Notch (NICD) or by coculture of parental HMEC with Notch ligand Dll4-or Jagged1-expressing HMEC at a 1:1 ratio (Dll4 or Jag1 coculture) (15,22).…”

Section: Activation Of Notch Induces Runx3 In Endothelial Cells-amentioning

confidence: 99%

RUNX3 Maintains the Mesenchymal Phenotype after Termination of the Notch Signal

Chang

Fournier

et al. 2011

Journal of Biological Chemistry

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Notch is a critical mediator of endothelial-to-mesenchymal transition (EndMT) during cardiac cushion development. Slug, a transcriptional repressor that is a Notch target, is an important Notch effector of EndMT in the cardiac cushion. Here, we report that the runt-related transcription factor RUNX3 is a novel direct Notch target in the endothelium. Ectopic expression of RUNX3 in endothelium induces Slug expression and EndMT independent of Notch activation. Interestingly, RUNX3 physically interacts with CSL, the Notch-interacting partner in the nucleus, and induces Slug in a CSL-dependent, but Notch-independent manner. Although RUNX3 may not be required for the initial induction of Slug and EndMT by Notch, because RUNX3 has a much longer half-life than Slug, it sustains the expression of Slug thereby maintaining the mesenchymal phenotype. CSL binds to the Runx3 promoter in the atrioventricular canal in vivo, and inhibition of Notch reduces RUNX3 expression in the cardiac cushion of embryonic hearts. Taken together, our results suggest that induction of RUNX3 may be a mechanism to maintain Notch-transformed mesenchymal cells during heart development.

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“…This significantly hampers our efforts to create in vitro or xeno-transplantation models. Unlike in the mouse system where ectopic expression of the HoxB4 gene can facilitate the generation of transplantable HSCs [50], no pathways have been identified that have the ability to push the human iPSC blood differentiation through primitive hematopoiesis stages, even though pathways such as NOTCH have been shown to be essential for HSC formation [51,52]. Insights from studies of early blood development in multiple animal models (e.g., mouse and zebrafish) will likely shed light on the molecular mechanisms of this process.…”

Section: Generation Of Functional Cell Types From Ipscsmentioning

confidence: 99%

Promise and challenges of human iPSC-based hematologic disease modeling and treatment

Chou

Cheng

2012

Int J Hematol

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Postnatal hematopoietic stem cells (HSCs) from umbilical cord blood and adult marrow/blood have been successfully used for treating various human diseases in the past several decades. However, the availability of optimal numbers of HSCs from autologous patients or allogeneic donors with adequate match remains a great barrier to improve and extend HSC and marrow transplantation to more needing patients. In addition, the inability to expand functional human HSCs to sufficient quantity in the laboratory has hindered our research and understanding of human HSCs and hematopoiesis. Recent development in reprogramming technology has provided patient-specific pluripotent stem cells (iPSCs) as a powerful enabling tool for modeling disease and developing therapeutics. Studies have demonstrated the potential of human iPSCs, which can be expanded exponentially and amenable for genome engineering, for using in modeling both inherited and acquired blood diseases. Proof-of-principle studies have also shown the feasibility of iPSCs in gene and cell therapy. Here, we review the recent development in iPSC-based blood disease modeling, and discuss the unsolved issues and challenges in this new and promising field.

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AML1/Runx1 rescues Notch1-null mutation-induced deficiency of para-aortic splanchnopleural hematopoiesis

Abstract: The Notch1-RBP-J and the transcription factor Runx1 pathways have been independently shown to be indispensable for the establishment of definitive hematopoiesis. Importantly, expression of Runx1 is down-regulated in the para-aortic splanchnopleural (P-Sp) region of Notch1-and

Cited by 84 publications

References 32 publications

The Notch pathway in the developing hematopoietic system

The Notch pathway in the developing hematopoietic system

RUNX3 Maintains the Mesenchymal Phenotype after Termination of the Notch Signal

Promise and challenges of human iPSC-based hematologic disease modeling and treatment

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