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Krueppel-like factor 15 regulates Wnt/beta-catenin transcription and controls cardiac progenitor cell fate in the postnatal heart

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Item Type:Article
Title:Krueppel-like factor 15 regulates Wnt/beta-catenin transcription and controls cardiac progenitor cell fate in the postnatal heart
Creators Name:Noack, C. and Zafiriou, M.P. and Schaeffer, H.J. and Renger, A. and Pavlova, E. and Dietz, R. and Zimmermann, W.H. and Bergmann, M.W. and Zelarayan, L.C.
Abstract:Wnt/beta-catenin signalling controls adult heart remodelling in part via regulation of cardiac progenitor cell (CPC) differentiation. An enhanced understanding of mechanisms controlling CPC biology might facilitate the development of new therapeutic strategies in heart failure. We identified and characterized a novel cardiac interaction between Krueppel-like factor 15 and components of the Wnt/beta-catenin pathway leading to inhibition of transcription. In vitro mutation, reporter assays and co-localization analyses revealed that KLF15 requires both the C-terminus, necessary for nuclear localization, and a minimal N-terminal regulatory region to inhibit transcription. In line with this, functional Klf15 knock-out mice exhibited cardiac beta-catenin transcriptional activation along with functional cardiac deterioration in normal homeostasis and upon hypertrophy. We further provide in vivo and in vitro evidences for preferential endothelial lineage differentiation of CPCs upon KLF15 deletion. Via inhibition of beta-catenin transcription, KLF15 controls CPC homeostasis in the adult heart similar to embryonic cardiogenesis. This knowledge may provide a tool for reactivation of this apparently dormant CPC population in the adult heart and thus be an attractive approach to enhance endogenous cardiac repair.
Keywords:Cardiac Progenitor Cell Fate, Endothelial Cells, Heart Remodelling, KLF15, Wnt Signalling, Animals, Mice
Source:EMBO Molecular Medicine
Page Range:992-1007
Date:September 2012
Official Publication:https://doi.org/10.1002/emmm.201101043
PubMed:View item in PubMed

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