Hematopoietic stem cell development requires transient Wnt/β-catenin activity

Ruiz-Herguido, Cristina; Guiu, Jordi; D’Altri, Teresa; Inglés-Esteve, Júlia; Dzierzak, Elaine; Espinosa, Lluís; Bigas, Anna

doi:10.1084/jem.20120225

Cited by 109 publications

(132 citation statements)

References 46 publications

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“…These results place the function of Chd1 downstream of the requirement for Wnt/β-catenin activity (35) and upstream of the activation of CD45. These data indicate that the earliest definitive hematopoietic progenitors form in Chd1 mutants but fail to expand in number and instead are lost by apoptosis.…”

Section: Discussionmentioning

confidence: 77%

“…However, the low percentage of endothelial cells that differentiate into hematopoietic cells and the technical difficulty in isolating these hemogenic clusters result in limited material available for analysis. Consequently, very little is known about how the endothelial-tohematopoietic transition occurs in vivo, and only a few genes or pathways, including Runx1 (7), Gata2 (13), Notch signaling (50), and the Wnt/β-catenin pathway (35), have been implicated in this process. Our study documents that Chd1 is the first chromatin remodeler, to our knowledge, shown to be essential for the emergence of HSPCs from the endothelium.…”

Section: Discussionmentioning

confidence: 99%

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Emergence of hematopoietic stem and progenitor cells involves a Chd1-dependent increase in total nascent transcription

Koh

Lizama

Wong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Lineage specification during development involves reprogramming of transcriptional states, but little is known about how this is regulated in vivo. The chromatin remodeler chomodomain helicase DNA-binding protein 1 (Chd1) promotes an elevated transcriptional output in mouse embryonic stem cells. Here we report that endothelial-specific deletion of Chd1 leads to loss of definitive hematopoietic progenitors, anemia, and lethality by embryonic day (E)15.5. Mutant embryos contain normal numbers of E10.5 intraaortic hematopoietic clusters that express Runx1 and Kit, but these clusters undergo apoptosis and fail to mature into blood lineages in vivo and in vitro. Hematopoietic progenitors emerging from the aorta have an elevated transcriptional output relative to structural endothelium, and this elevation is Chd1-dependent. In contrast, hematopoietic-specific deletion of Chd1 using Vav-Cre has no apparent phenotype. Our results reveal a new paradigm of regulation of a developmental transition by elevation of global transcriptional output that is critical for hemogenesis and may play roles in other contexts.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Emergence of hematopoietic stem and progenitor cells involves a Chd1-dependent increase in total nascent transcription

Koh

Lizama

Wong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, the PKA-CREB signaling pathway has been explored in the context of the prostaglandin E 2 signaling pathway in zebrafish, where it promotes AGM hematopoiesis via activation of the Wnt pathway ). However, whether this pathway is conserved in the mouse is unclear, especially given conflicting reports on Wnt signaling in AGM hematopoiesis (Ruiz-Herguido et al, 2012;Chanda et al, 2013). Prostaglandin E 2 also directly activates several pathways including PI3K-AKT and ERK-MAPK, which makes it difficult to conclude that PKA-CREB is the sole mediator of the pro-hematopoietic effects of this molecule (Alfranca et al, 2006).…”

Section: Genomic Binding and Interaction Of Creb In K562 Cellsmentioning

confidence: 99%

Flow-induced protein kinase A–CREB pathway acts via BMP signaling to promote HSC emergence

Kim¹,

Nakano²,

Das³

et al. 2015

J Cell Biol

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Fluid shear stress promotes the emergence of hematopoietic stem cells (HSCs) in the aortagonad-mesonephros (AGM) of the developing mouse embryo. We determined that the AGM is enriched for expression of targets of protein kinase A (PKA)-cAMP response elementbinding protein (CREB), a pathway activated by fluid shear stress. By analyzing CREB genomic occupancy from chromatin-immunoprecipitation sequencing (ChIP-seq) data, we identified the bone morphogenetic protein (BMP) pathway as a potential regulator of CREB. By chemical modulation of the PKA-CREB and BMP pathways in isolated AGM VEcadherin + cells from mid-gestation embryos, we demonstrate that PKA-CREB regulates hematopoietic engraftment and clonogenicity of hematopoietic progenitors, and is dependent on secreted BMP ligands through the type I BMP receptor. Finally, we observed blunting of this signaling axis using Ncx1-null embryos, which lack a heartbeat and intravascular flow. Collectively, we have identified a novel PKA-CREB-BMP signaling pathway downstream of shear stress that regulates HSC emergence in the AGM via the endothelial-tohematopoietic transition.

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“…Notch (Burns et al, 2005;Butko et al, 2016;Clements and Traver, 2013;Gering and Patient, 2010;Lawson et al, 2001), Bone morphogenetic protein (Bmp) (Wilkinson et al, 2009), Wnt (Goessling et al, 2009;Luis and Staal, 2009;North et al, 2007;Ruiz-Herguido et al, 2012), Shh Gering and Patient, 2005;Lawson et al, 2002;Wilkinson et al, 2009), Vegfa (Burns et al, 2005;Patient, 2005, 2010;Lawson et al, 2003), and Tgfβ (Monteiro et al, 2016) all contribute to HSC program initiation.…”

Section: Introductionmentioning

confidence: 99%

R-spondin 1 is required for specification of hematopoietic stem cells through Wnt16 and Vegfa signaling pathways

Genthe

Clements

2017

Development

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Hematopoietic stem cells (HSCs) are the therapeutic component of bone marrow transplants, but finding immune-compatible donors limits treatment availability and efficacy. Recapitulation of endogenous specification during development is a promising approach to directing HSC specification in vitro, but current protocols are not capable of generating authentic HSCs with high efficiency. Across phyla, HSCs arise from hemogenic endothelium in the ventral floor of the dorsal aorta concurrent with arteriovenous specification and intersegmental vessel (ISV) sprouting, processes regulated by Notch and Wnt. We hypothesized that coordination of HSC specification with vessel patterning might involve modulatory regulatory factors such as R-spondin 1 (Rspo1), an extracellular protein that enhances β-catenin-dependent Wnt signaling and has previously been shown to regulate ISV patterning. We find that Rspo1 is required for HSC specification through control of parallel signaling pathways controlling HSC specification: Wnt16/DeltaC/DeltaD and Vegfa/Tgfβ1. Our results define Rspo1 as a key upstream regulator of two crucial pathways necessary for HSC specification.

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Hematopoietic stem cell development requires transient Wnt/β-catenin activity

Abstract: Deletion of β-catenin from mouse embryonic endothelium, but not embryonic hematopoietic cells, prevents hematopoietic differentiation; thus Wnt/β-catenin signaling is needed for emergence but not maintenance of HSCs.

Cited by 109 publications

References 46 publications

Emergence of hematopoietic stem and progenitor cells involves a Chd1-dependent increase in total nascent transcription

Emergence of hematopoietic stem and progenitor cells involves a Chd1-dependent increase in total nascent transcription

Flow-induced protein kinase A–CREB pathway acts via BMP signaling to promote HSC emergence

R-spondin 1 is required for specification of hematopoietic stem cells through Wnt16 and Vegfa signaling pathways

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