Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Cell
2008 Dec 12;1356:1053-64. doi: 10.1016/j.cell.2008.10.049.
Show Gene links
Show Anatomy links
Combinatorial regulation of endothelial gene expression by ets and forkhead transcription factors.
De Val S
,
Chi NC
,
Meadows SM
,
Minovitsky S
,
Anderson JP
,
Harris IS
,
Ehlers ML
,
Agarwal P
,
Visel A
,
Xu SM
,
Pennacchio LA
,
Dubchak I
,
Krieg PA
,
Stainier DY
,
Black BL
.
???displayArticle.abstract???
Vascular development begins when mesodermal cells differentiate into endothelial cells, which then form primitive vessels. It has been hypothesized that endothelial-specific gene expression may be regulated combinatorially, but the transcriptional mechanisms governing specificity in vascular gene expression remain incompletely understood. Here, we identify a 44 bp transcriptional enhancer that is sufficient to direct expression specifically and exclusively to the developing vascular endothelium. This enhancer is regulated by a composite cis-acting element, the FOX:ETS motif, which is bound and synergistically activated by Forkhead and Ets transcription factors. We demonstrate that coexpression of the Forkhead protein FoxC2 and the Ets protein Etv2 induces ectopic expression of vascular genes in Xenopus embryos, and that combinatorial knockdown of the orthologous genes in zebrafish embryos disrupts vascular development. Finally, we show that FOX:ETS motifs are present in many known endothelial-specific enhancers and that this motif is an efficient predictor of endothelial enhancers in the human genome.
Figure 3. Misexpression of FoxC2 and Etv2 in Xenopus Embryos Induces Ectopic Endothelial Gene ExpressionXenopus embryos were injected with mRNAs encoding FoxC2 and Etv2 or EGFP control mRNA at the 4-cell stage and then collected at stage 36. After collection, embryos were either assayed by in situ hybridization using flk1 probe, followed by sectioning (A and B), or RNA was extracted for qPCR analysis of flk1 (C) or Pecam (D) transcripts. (A and B) flk1 expression was observed in the cardinal veins (CVs) in control (A) and FoxC2 + Etv2-injected (B) embryos. In addition, ectopic expression of flk1 was readily observed in the endoderm of the caudal region of FoxC2 + Etv2-injected embryos (B) but not in EGFP control injected embryos (A).(C and D) Quantitative, real-time PCR shows that neither FoxC2 nor Etv2 significantly activated flk1 or Pecam expression on their own, but the combination of the two factors strongly induced expression of both endothelial-specific markers. Data are shown as the mean relative expression of flk1 or Pecam transcripts for three independent sets of injections and analyses. Error bars indicate the SEM.
Andreoli,
Anti-vascular endothelial growth factor therapy for ocular neovascular disease.
2007,
Pubmed
Baron,
Embryonic origins of mammalian hematopoiesis.
2003,
Pubmed
Carlsson,
Forkhead transcription factors: key players in development and metabolism.
2002,
Pubmed
Carmeliet,
Angiogenesis in cancer and other diseases.
2000,
Pubmed
Cleaver,
Neovascularization of the Xenopus embryo.
1997,
Pubmed
,
Xenbase
Dejana,
Foxs and Ets in the transcriptional regulation of endothelial cell differentiation and angiogenesis.
2007,
Pubmed
De Val,
Mef2c is activated directly by Ets transcription factors through an evolutionarily conserved endothelial cell-specific enhancer.
2004,
Pubmed
Dube,
Role of the Ets transcription factors in the regulation of the vascular-specific Tie2 gene.
1999,
Pubmed
Flamme,
Molecular mechanisms of vasculogenesis and embryonic angiogenesis.
1997,
Pubmed
Furuyama,
Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice.
2004,
Pubmed
Goh,
Molecular and cellular regulators of cancer angiogenesis.
2007,
Pubmed
Göttgens,
Establishing the transcriptional programme for blood: the SCL stem cell enhancer is regulated by a multiprotein complex containing Ets and GATA factors.
2002,
Pubmed
,
Xenbase
Hallikas,
Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity.
2006,
Pubmed
Hollenhorst,
Expression profiles frame the promoter specificity dilemma of the ETS family of transcription factors.
2004,
Pubmed
Hollenhorst,
Genome-wide analyses reveal properties of redundant and specific promoter occupancy within the ETS gene family.
2007,
Pubmed
Hosaka,
Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification.
2004,
Pubmed
Jin,
Cellular and molecular analyses of vascular tube and lumen formation in zebrafish.
2005,
Pubmed
,
Xenbase
Kappel,
Identification of vascular endothelial growth factor (VEGF) receptor-2 (Flk-1) promoter/enhancer sequences sufficient for angioblast and endothelial cell-specific transcription in transgenic mice.
1999,
Pubmed
Lin,
Requirement of the MADS-box transcription factor MEF2C for vascular development.
1998,
Pubmed
Loots,
rVista for comparative sequence-based discovery of functional transcription factor binding sites.
2002,
Pubmed
Markstein,
Genome-wide analysis of clustered Dorsal binding sites identifies putative target genes in the Drosophila embryo.
2002,
Pubmed
Maroulakou,
Expression and function of Ets transcription factors in mammalian development: a regulatory network.
2000,
Pubmed
Patan,
Vasculogenesis and angiogenesis.
2004,
Pubmed
Pennacchio,
In vivo enhancer analysis of human conserved non-coding sequences.
2006,
Pubmed
Pham,
Combinatorial function of ETS transcription factors in the developing vasculature.
2007,
Pubmed
Prandini,
The human VE-cadherin promoter is subjected to organ-specific regulation and is activated in tumour angiogenesis.
2005,
Pubmed
Pruitt,
NCBI Reference Sequence (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins.
2005,
Pubmed
Rojas,
GATA4 is a direct transcriptional activator of cyclin D2 and Cdk4 and is required for cardiomyocyte proliferation in anterior heart field-derived myocardium.
2008,
Pubmed
Sato,
Role of ETS family transcription factors in vascular development and angiogenesis.
2001,
Pubmed
Seo,
The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development.
2006,
Pubmed
,
Xenbase
Simó,
Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy.
2006,
Pubmed
Stacker,
The role of tumor lymphangiogenesis in metastatic spread.
2002,
Pubmed
Sumanas,
Interplay among Etsrp/ER71, Scl, and Alk8 signaling controls endothelial and myeloid cell formation.
2008,
Pubmed
Sumanas,
Ets1-related protein is a key regulator of vasculogenesis in zebrafish.
2006,
Pubmed
Topczewska,
Sequence and expression of zebrafish foxc1a and foxc1b, encoding conserved forkhead/winged helix transcription factors.
2001,
Pubmed
Traver,
Transplantation and in vivo imaging of multilineage engraftment in zebrafish bloodless mutants.
2003,
Pubmed
Wu,
Molecular determinants of NOTCH4 transcription in vascular endothelium.
2005,
Pubmed
