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The four and a half LIM-domain (FHL) 2 controls early cardiac cell commitment and expansion via regulating beta-catenin-dependent transcription

Item Type:Article
Title:The four and a half LIM-domain (FHL) 2 controls early cardiac cell commitment and expansion via regulating beta-catenin-dependent transcription
Creators Name:Renger, A. and Zafiriou, M.P. and Noack, C. and Pavlova, E. and Becker, A. and Sharkova, K. and Bergmann, M.W. and El-Armouche, A. and Zimmermann, W.H. and Zelarayan, L.C.
Abstract:INTRODUCTION: The multiphasic regulation of the Wnt/beta-catenin canonical pathway is essential for cardiogenesis in vivo and in vitro. To achieve tight regulation of the Wnt/beta-catenin signaling, tissue- and cell-specific co-activators and -repressors need to be recruited. The identification of such factors may help to elucidate mechanisms leading to enhanced cardiac differentiation efficiency in vitro as well as promote regeneration in vivo. RESULTS: Using a yeast-two-hybrid screen, we identified FHL2 as a cardiac specific beta-catenin interaction partner and activator of Wnt/beta-catenin-dependent transcription. We analyzed the role of this interaction for early cardiogenesis in an in vitro model by making use of embryoid body cultures from mouse embryonic stem cells (ESCs). In this model, stable FHL2 gain-of-function promoted mesodermal cell formation and cell proliferation while arresting cardiac differentiation in an early cardiogenic mesodermal progenitor state. Mechanistically, FHL2 overexpression enhanced nuclear accumulation of beta-catenin and activated Wnt/beta-catenin-dependent transcription leading to sustained up-regulation of the early cardiogenic gene Igfbp5. In an alternative P19 cell model, transient FHL2 overexpression led to early activation of Wnt/beta-catenin-dependent transcription, but not sustained high-level of Igfbp5 expression. This resulted in enhanced cardiogenesis. CONCLUSION: We propose that early Wnt/beta-catenin-dependent transcriptional activation mediated by FHL2 is important for the transition to and expansion of early cardiogenic mesodermal cells. Collectively, our findings offer mechanistic insight into the early cardiogenic code and may be further exploited to enhance cardiac progenitor cell activity in vitro and in vivo.
Keywords:FHL2, beta-catenin, Igfbp5, mESC, Cardiogenesis, Animals, Mice
Source:Stem Cells
ISSN:1066-5099
Publisher:Wiley-Blackwell (U.S.A.)
Volume:31
Number:5
Page Range:928-940
Date:May 2013
Official Publication:https://doi.org/10.1002/stem.1332
PubMed:View item in PubMed

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