title: The four and a half LIM-domain 2 controls early cardiac cell commitment and expansion via regulating β-catenin-dependent transcription.
abstract: The multiphasic regulation of the Wnt/β-catenin canonical pathway is essential for cardiogenesis in vivo and in vitro. To achieve tight regulation of the Wnt/β-catenin signaling, tissue- and cell-specific coactivators 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. Using a yeast-two-hybrid screen, we identified four-and-a-half-LIM-domain 2 (FHL2) as a cardiac-specific β-catenin interaction partner and activator of Wnt/β-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 β-catenin and activated Wnt/β-catenin-dependent transcription leading to sustained upregulation of the early cardiogenic gene Igfbp5. In an alternative P19 cell model, transient FHL2 overexpression led to early activation of Wnt/β-catenin-dependent transcription, but not sustained high-level of Igfbp5 expression. This resulted in enhanced cardiogenesis. We propose that early Wnt/β-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.
authors: Department of Pharmacology and, Heart Research Center Göttingen (HRCG), University Medical Center-Georg-August-University-Göttingen, Göttingen, Germany.
authors: Anke
authors: A
authors: Renger
authors: Maria-Patapia
authors: MP
authors: Zafiriou
authors: Claudia
authors: C
authors: Noack
authors: Elena
authors: E
authors: Pavlova
authors: Alexander
authors: A
authors: Becker
authors: Krasimira
authors: K
authors: Sharkova
authors: Martin W
authors: MW
authors: Bergmann
authors: Ali
authors: A
authors: El-Armouche
authors: Wolfram-Hubertus
authors: WH
authors: Zimmermann
authors: Laura C
authors: LC
authors: Zelarayán
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D060850:LIM-Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
chemical_list: C491382:Fhl2 protein, mouse; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors; D051176:beta Catenin