Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on hemogenic endothelium

Jang, Il Ho; Lü, Yi; Zhao, Long; Wenzel, Pamela L.; Kume, Tsutomu; Datta, Sumon; Arora, Natasha; Guiu, Jordi; Lagha, Mounia; Kim, Peter G.; Kyoung, Eun; Kim, Jae Ho; Schlaeger, Thorsten M.; Zon, Leonard I.; Bigas, Anna; Burns, Caroline E.; Daley, George Q.

doi:10.1182/blood-2014-04-568170

Cited by 42 publications

(51 citation statements)

References 58 publications

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“…Indeed, most of the emerging hemogenic endothelial cells as defined by Sca1-GFP are also phospho-CREB + . Interestingly, activation of PKA results in up-regulation of Foxc2, which has been recently identified to play a role in the hemogenic endothelium (Jang et al, 2015). The endothelial-tohematopoietic transition has garnered recent interest because lineage tracing and live-imaging studies have shown that HSCs emerge from the VE-cadherin + vascular endothelium in the AGM (Chen et al, 2009;Bertrand et al, 2010;Boisset et al, 2010).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Relative to the FL and BM, the AGM is enriched in IL-3 and IL-6 signaling pathways, 3,24 which in concert with other pathways such as Notch signaling, participate in hematopoietic emergence. 19,43 The AGM is enriched for shear-stress-mediated PGE2 and protein kinase A/cAMP-responsive element-binding protein signaling, [44][45][46] which can activate IL-6. [47][48][49] Subsequently, through exposure to IFN-a during maturation in the FL, AGM HSCs acquire expanded potential for engraftment in adults.…”

Section: Discussionmentioning

confidence: 99%

Interferon-α signaling promotes embryonic HSC maturation

Kim

Canver

Rhee

et al. 2016

Blood

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In the developing mouse embryo, the first hematopoietic stem cells (HSCs) arise in the aorta-gonad-mesonephros (AGM) and mature as they transit through the fetal liver (FL). Compared with FL and adult HSCs, AGM HSCs have reduced repopulation potential in irradiated adult transplant recipients but mechanisms underlying this deficiency in AGM HSCs are poorly understood. By co-expression gene network analysis, we deduced that AGM HSCs show lower levels of interferon-a (IFN-a)/Jak-Stat1-associated gene expression than FL HSCs. Treatment of AGM HSCs with IFN-a enhanced long-term hematopoietic engraftment and donor chimerism. Conversely, IFN-a receptor-deficient AGMs (Ifnar1 2/2 ), had significantly reduced donor chimerism. We identify adenine-thymine-rich interactive domain-3a (Arid3a), a factor essential for FL and B lymphopoiesis, as a key transcriptional co-regulator of IFN-a/Stat1 signaling. Arid3a occupies the genomic loci of Stat1 as well as several IFN-a effector genes, acting to regulate their expression. Accordingly, Arid3a 2/2 AGM HSCs had significantly reduced transplant potential, which was rescued by IFN-a treatment. Our results implicate the inflammatory IFN-a/ Jak-Stat pathway in the developmental maturation of embryonic HSCs, whose manipulation may lead to increased potency of reprogrammed HSCs for transplantation. (Blood. 2016;128(2):204-216)

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“…[33][34][35] Notch2 knockouts show no obvious hematopoietic defects 33 and Notch3 and Notch4 knockouts are viable, indicating their nonessential role in HSC development. 43,47 The requirement for Notch in the endothelial-hematopoietic transition is conserved in zebrafish, 19,[48][49][50][51] where Notch1 acts through activation of and cooperation with important transcription factors such as Gata2, Runx1, Scl, Foxc2, and Hes1/5. 34,48,[50][51][52][53][54] Although Notch is essential for early HSC development, exact stage-specific requirements for this signaling pathway in this multistep maturation process remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Developing HSCs become Notch independent by the end of maturation in the AGM region

Souilhol

Lendinez

Rybtsov

et al. 2016

Blood

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Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on hemogenic endothelium

Abstract: Key Points Notch1 induction promotes specification of hemogenic endothelial cells during embryonic stem cell differentiation. Foxc2 functions downstream of Notch in specification of hemogenic endothelium in mouse and zebrafish embryos.

Cited by 42 publications

References 58 publications

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

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

Interferon-α signaling promotes embryonic HSC maturation

Developing HSCs become Notch independent by the end of maturation in the AGM region

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