Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling

Guiu, Jordi; Shimizu, Ritsuko; D’Altri, Teresa; Fraser, Stuart T.; Hatakeyama, Jun; Bresnick, Emery H.; Kageyama, Ryoichiro; Dzierzak, Elaine; Yamamoto, Masayuki; Espinosa, Lluís; Bigas, Anna

doi:10.1083/jcb2001oia1

Cited by 31 publications

(43 citation statements)

References 30 publications

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“…In mouse, both GATA2 and NOTCH1 are required cellautonomously for formation of HSCs (Hadland et al, 2004;Tsai et al, 1994). The transcriptionally active NOTCH1 intracellular domain (NICD1) associates with the Gata2 promoter in the mouse embryo at E9.5, just before HSC emergence, and is required for Gata2 expression in the DA (Guiu et al, 2013;Robert-Moreno et al, 2005). These findings suggest that Gata2 is a direct target of a cell-autonomous Notch signal within hemogenic endothelium.…”

Section: Regulation Of Gata2b Expressionmentioning

confidence: 79%

Gata2b is a restricted early regulator of hemogenic endothelium in the zebrafish embryo

et al. 2015

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The adult blood system is established by hematopoietic stem cells (HSCs), which arise during development from an endothelial-tohematopoietic transition of cells comprising the floor of the dorsal aorta. Expression of aortic runx1 has served as an early marker of HSC commitment in the zebrafish embryo, but recent studies have suggested that HSC specification begins during the convergence of posterior lateral plate mesoderm (PLM), well before aorta formation and runx1 transcription. Further understanding of the earliest stages of HSC specification necessitates an earlier marker of hemogenic endothelium. Studies in mice have suggested that GATA2 might function at early stages within hemogenic endothelium. Two orthologs of Gata2 exist in zebrafish: gata2a and gata2b. Here, we report that gata2b expression initiates during the convergence of PLM, becoming restricted to emerging HSCs. We observe Notch-dependent gata2b expression within the hemogenic subcompartment of the dorsal aorta that is in turn required to initiate runx1 expression. Our results indicate that Gata2b functions within hemogenic endothelium from an early stage, whereas Gata2a functions more broadly throughout the vascular system.

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Section: Regulation Of Gata2b Expressionmentioning

confidence: 79%

Gata2b is a restricted early regulator of hemogenic endothelium in the zebrafish embryo

et al. 2015

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“…It has been shown that, although Hes1-deficient mice do not show clear abnormalities in their hematopoietic system, the depletion of both Hes1 and Hes5 induces overproduction of nonfunctional HSCs, in which Hes target genes such as Gata2 are abnormally up-regulated (Guiu et al, 2013). Hes1 is also reported to be an important regulator of the development of T cell acute lymphoblastic leukemia (Espinosa et al, 2010;Wendorff et al, 2010).…”

Section: Forced Expression Of Hes1 Results In Increased Numbers Of Qumentioning

confidence: 99%

Expression Dynamics and Functions of Hes Factors in Development and Diseases

Kobayashi

Kageyama

2014

Current Topics in Developmental Biology

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Hes genes, encoding basic helix-loop-helix (HLH) transcriptional repressors, are mammalian homologues of Drosophila hairy and Enhancer of split genes, both of which are required for normal neurogenesis in Drosophila. There are seven members in the human Hes family, Hes1 to Hes7, which are expressed in many tissues and play various roles mainly in development. All Hes proteins have three conserved domains: basic HLH (bHLH), Orange, and WRPW domains. The basic region binds to target DNA sequences while the HLH region forms homo-and hetero-dimers with other bHLH proteins, the Orange domain is responsible for the selection of partners during heterodimer formation, and the WRPW domain recruits co-repressors. Hes1, Hes5, and Hes7 are known as downstream effectors of canonical Notch signaling, which regulates cell differentiation via cell-cell interaction. Hes factors regulate many events in development by repressing the expression of target genes, many of which encode transcriptional activators that promote cell differentiation. For example, Hes1, Hes3, and Hes5 are highly expressed by neural stem cells, and inactivation of these genes results in insufficient maintenance of stem cell proliferation and prematurely promotes neuronal differentiation. Recently, it was shown that the expression dynamics of Hes1 plays crucial roles in proper developmental timings and fate determination steps of embryonic stem cells and neural progenitor cells. Here we discuss some key features of Hes factors in development and diseases.

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“…69 Notch activity is downregulated in hematopoietic clusters while maintained in the aortic endothelium, and expression of Notch target Hes1 decreases during the endothelia-to-hematopoietic transition. 52,[70][71][72][73][74] Furthermore, lowering Notch activity is required for suppression of the arterial program and acquisition of the hematopoietic fate. 71,73 A recent report has also indicated that Notch signaling in HSCs is lower than in the aortic structural endothelium.…”

Section: Rbp-jκmentioning

confidence: 99%

“…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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Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling

Cited by 31 publications

References 30 publications

Gata2b is a restricted early regulator of hemogenic endothelium in the zebrafish embryo

Gata2b is a restricted early regulator of hemogenic endothelium in the zebrafish embryo

Expression Dynamics and Functions of Hes Factors in Development and Diseases

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

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