title: Krueppel-like factor 15 regulates Wnt/β-catenin transcription and controls cardiac progenitor cell fate in the postnatal heart.
abstract: Wnt/β-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/β-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 β-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 β-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.
authors: Heart Research Center Göttingen, University Medical Center Göttingen, Georg-August-University Göttingen, Germany.
authors: Claudia
authors: C
authors: Noack
authors: Maria-Patapia
authors: MP
authors: Zafiriou
authors: Hans-Joerg
authors: HJ
authors: Schaeffer
authors: Anke
authors: A
authors: Renger
authors: Elena
authors: E
authors: Pavlova
authors: Rainer
authors: R
authors: Dietz
authors: Wolfram H
authors: WH
authors: Zimmermann
authors: Martin W
authors: MW
authors: Bergmann
authors: Laura C
authors: LC
authors: Zelarayán
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D013234:Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D004268:DNA-Binding Proteins; C467418:Klf15 protein, mouse; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin