Inhibition of endothelial ERK signalling by Smad1/5 is essential for haematopoietic stem cell emergence

Zhang, Chun Xia; Lv, Juan; He, Qiuping; Wang, Sifeng; Gao, Yinjie; Meng, Anming; Yang, Xiao; Liu, Feng

doi:10.1038/ncomms4431

Cited by 42 publications

(41 citation statements)

References 53 publications

(78 reference statements)

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“…WNT signalling via β-catenin is essential for the generation of the hemogenic endothelium (Ruiz-Herguido et al, 2012). Catecholamines from the sympathetic nervous system are important components of the developing HSC microenvironment (Fitch et al, 2012) and BMP4 signalling leads to a SMAD1/5-mediated repression of Erk transcription in HE cells, implying a role for mitogen-activated protein kinase (MAPK) signalling in these cells (Zhang et al, 2014). The specification of HSCs from the hemogenic endothelium is a tightly regulated biological process that is controlled by dynamic changes of signalling and TF activity.…”

Section: Discussionmentioning

confidence: 99%

Cooperative binding of AP-1 and TEAD4 modulates the balance between vascular smooth muscle and hemogenic cell fate

et al. 2016

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The transmission of extracellular signals into the nucleus involves inducible transcription factors, but how different signalling pathways act in a cell type-specific fashion is poorly understood. Here, we studied the regulatory role of the AP-1 transcription factor family in blood development using embryonic stem cell differentiation coupled with genome-wide transcription factor binding and gene expression analyses. AP-1 factors respond to MAP kinase signalling and comprise dimers of FOS, ATF and JUN proteins. To examine genes regulated by AP-1 and to examine how it interacts with other inducible transcription factors, we abrogated its global DNA-binding activity using a dominant-negative FOS peptide. We show that FOS and JUN bind to and activate a specific set of vascular genes and that AP-1 inhibition shifts the balance between smooth muscle and hematopoietic differentiation towards blood. Furthermore, AP-1 is required for de novo binding of TEAD4, a transcription factor connected to Hippo signalling. Our bottom-up approach demonstrates that AP-1- and TEAD4-associated cis-regulatory elements form hubs for multiple signalling-responsive transcription factors and define the cistrome that regulates vascular and hematopoietic development by extrinsic signals.

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Section: Discussionmentioning

confidence: 99%

Cooperative binding of AP-1 and TEAD4 modulates the balance between vascular smooth muscle and hemogenic cell fate

et al. 2016

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“…To our knowledge, this is the first study linking ETS and GATA factors to the regulation of BMP pathway activity in endothelial cells and provides an important framework to study the relationship in other contexts where both are crucial, including blood development (38,39).…”

Section: Discussionmentioning

confidence: 99%

SMAD1 and SMAD5 Expression Is Coordinately Regulated by FLI1 and GATA2 during Endothelial Development

Marks-Bluth

Khanna

Chandrakanthan

et al. 2015

Molecular and Cellular Biology

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hThe bone morphogenetic protein (BMP)/SMAD signaling pathway is a critical regulator of angiogenic sprouting and is involved in vascular development in the embryo. SMAD1 and SMAD5, the core mediators of BMP signaling, are vital for this activity, yet little is known about their transcriptional regulation in endothelial cells. Here, we have integrated multispecies sequence conservation, tissue-specific chromatin, in vitro reporter assay, and in vivo transgenic data to identify and validate Smad1؉63 and the Smad5 promoter as tissue-specific cis-regulatory elements that are active in the developing endothelium. The activity of these elements in the endothelium was dependent on highly conserved ETS, GATA, and E-box motifs, and chromatin immunoprecipitation showed high levels of enrichment of FLI1, GATA2, and SCL at these sites in endothelial cell lines and E11 dorsal aortas in vivo. Knockdown of FLI1 and GATA2 but not SCL reduced the expression of SMAD1 and SMAD5 in endothelial cells in vitro. In contrast, CD31؉ cKit ؊ endothelial cells harvested from embryonic day 9 (E9) aorta-gonad-mesonephros (AGM) regions of GATA2 null embryos showed reduced Smad1 but not Smad5 transcript levels. This is suggestive of a degree of in vivo selection where, in the case of reduced SMAD1 levels, endothelial cells with more robust SMAD5 expression have a selective advantage.

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“…This is highly similar to the ERK signaling in the AGM region where its finely controlled threshold is crucial for HSC emergence in vertebrates. 39 The dosage sensitive role of fos levels in HSC emergence is currently unclear. A recent report showed that c-Fos, plus 3 other transcription factors are sufficient to convert mouse fibroblasts into hemogenic endothelium, 4 suggesting that c-Fos can promote HSC emergence.…”

Section: Discussionmentioning

confidence: 99%

Ncor2 is required for hematopoietic stem cell emergence by inhibiting Fos signaling in zebrafish

Wei

Gao

et al. 2014

Blood

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Inhibition of endothelial ERK signalling by Smad1/5 is essential for haematopoietic stem cell emergence

Cited by 42 publications

References 53 publications

Cooperative binding of AP-1 and TEAD4 modulates the balance between vascular smooth muscle and hemogenic cell fate

Cooperative binding of AP-1 and TEAD4 modulates the balance between vascular smooth muscle and hemogenic cell fate

SMAD1 and SMAD5 Expression Is Coordinately Regulated by FLI1 and GATA2 during Endothelial Development

Ncor2 is required for hematopoietic stem cell emergence by inhibiting Fos signaling in zebrafish

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