Letter abstract
Nature Cell Biology 10, 338 - 345 (2008)
Published online: 24 February 2008 | doi:10.1038/ncb1696
MesP1 drives vertebrate cardiovascular differentiation through Dkk-1-mediated blockade of Wnt-signalling
R. David1, C. Brenner1, J. Stieber2, F. Schwarz1, S. Brunner1, M. Vollmer3, E. Mentele4, J. Müller-Höcker5, S. Kitajima6, H. Lickert3, R. Rupp4 & W.-M. Franz1
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 MesP11, 2. As one of the earliest markers, it is expressed specifically in almost all cardiovascular precursors and is required for cardiac morphogenesis2, 3. 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 differentiation4. 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.
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Medizinische Klinik und Poliklinik I, Klinikum Gro
hadern der LMU, D-81377 München, Germany. - Lehrstuhl für Pharmakologie und Toxikologie der Universität Erlangen, D-91054 Erlangen, Germany
- GSF - National Research Center for Environment and Health, D-85764 Neuherberg, Germany.
- Adolph-Butenandt-Institut der LMU, D-80336 München, Germany.
- Pathologisches Institut der LMU, D-80337 München, Germany.
- Division of Cellular & Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences 1-18-1 Kamiyohga, Setagaya-ku, Tokyo 158-8501, Japan.
Correspondence to: R. David1 e-mail: robert.david@med.uni-muenchen.de
Correspondence to: W.-M. Franz1 e-mail: wolfgang.franz@med.uni-muenchen.de
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