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PMID:18297060

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Citation

David, R, Brenner, C, Stieber, J, Schwarz, F, Brunner, S, Vollmer, M, Mentele, E, Müller-Höcker, J, Kitajima, S, Lickert, H, Rupp, R and Franz, WM (2008) MesP1 drives vertebrate cardiovascular differentiation through Dkk-1-mediated blockade of Wnt-signalling. Nat. Cell Biol. 10:338-45

Abstract

ES-cell-based cardiovascular repair requires an in-depth understanding of the molecular mechanisms underlying the differentiation of cardiovascular ES cells. A candidate cardiovascular-fate inducer is the bHLH transcription factor MesP1. As one of the earliest markers, it is expressed specifically in almost all cardiovascular precursors and is required for cardiac morphogenesis. Here we show that MesP1 is a key factor sufficient to induce the formation of ectopic heart tissue in vertebrates and increase cardiovasculogenesis by ES cells. Electrophysiological analysis showed all subtypes of cardiac ES-cell differentiation. MesP1 overexpression and knockdown experiments revealed a prominent function of MesP1 in a gene regulatory cascade, causing Dkk-1-mediated blockade of canonical Wnt-signalling. Independent evidence from ChIP and in vitro DNA-binding studies, expression analysis in wild-type and MesP knockout mice, and reporter assays confirm that Dkk-1 is a direct target of MesP1. Further analysis of the regulatory networks involving MesP1 will be required to preprogramme ES cells towards a cardiovascular fate for cell therapy and cardiovascular tissue engineering. This may also provide a tool to elicit cardiac transdifferentiation in native human adult stem cells.

Links

PubMed Online version:10.1038/ncb1696

Keywords

Animals; Basic Helix-Loop-Helix Transcription Factors/metabolism; Basic Helix-Loop-Helix Transcription Factors/physiology; Cell Differentiation; Chromatin Immunoprecipitation; Embryonic Stem Cells/cytology; Endothelium, Vascular/metabolism; Gene Expression Regulation; Humans; Intercellular Signaling Peptides and Proteins/metabolism; Intercellular Signaling Peptides and Proteins/physiology; Mice; Mice, Knockout; Models, Biological; Signal Transduction; Wnt Proteins/metabolism; Xenopus laevis/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:DKK1

involved_in

GO:0090082: positive regulation of heart induction by negative regulation of canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MESP1

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:MESP1

enables

GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0001952)

Seeded From UniProt

complete

MOUSE:MESP1

enables

GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific

ECO:0000315: mutant phenotype evidence used in manual assertion

F

  • occurs_at:(SO:0001952)

Seeded From UniProt

complete

MOUSE:MESP1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(NCBI_Gene:13380)

Seeded From UniProt

complete

MOUSE:MESP1

involved_in

GO:0003259: cardioblast anterior-lateral migration

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MESP1

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:MESP1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MESP1

involved_in

GO:0090082: positive regulation of heart induction by negative regulation of canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MESP1

involved_in

GO:0022008: neurogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MESP1

located_in

GO:0005634: nucleus

ECO:0000305: curator inference used in manual assertion

GO:0000976

C

Seeded From UniProt

complete

HUMAN:MESP1

involved_in

GO:0003211: cardiac ventricle formation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MESP1

involved_in

GO:0003210: cardiac atrium formation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MESP1

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MESP1

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MESP1

involved_in

GO:0060947: cardiac vascular smooth muscle cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MESP1

involved_in

GO:0060921: sinoatrial node cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MESP1

involved_in

GO:0055007: cardiac muscle cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MESP1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MESP1

involved_in

GO:0045446: endothelial cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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