ZFIN ID: ZDB-PUB-120106-28
Discovering Small Molecules that Promote Cardiomyocyte Generation by Modulating Wnt Signaling
Ni, T.T., Rellinger, E.J., Mukherjee, A., Xie, S., Stephens, L., Thorne, C.A., Kim, K., Hu, J., Lee, E., Marnett, L., Hatzopoulos, A.K., and Zhong, T.P.
Date: 2011
Source: Chemistry & Biology   18(12): 1658-1668 (Journal)
Registered Authors: Zhong, Tao P.
Keywords: none
MeSH Terms:
  • Animals
  • Cell Differentiation/drug effects*
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/metabolism
  • Embryonic Development
  • Embryonic Stem Cells/cytology*
  • Embryonic Stem Cells/metabolism
  • Heart/drug effects
  • Heart/growth & development
  • Mice
  • Myocytes, Cardiac/drug effects
  • Myocytes, Cardiac/metabolism*
  • Signal Transduction/drug effects
  • Thiadiazoles/chemistry
  • Thiadiazoles/pharmacology*
  • Triazoles/chemistry
  • Triazoles/pharmacology*
  • Wnt Proteins/metabolism*
  • Zebrafish
  • Zebrafish Proteins/metabolism*
  • beta Catenin/metabolism
PubMed: 22195568 Full text @ Chem. Biol.
We have developed a robust in vivo small-molecule screen that modulates heart size and cardiomyocyte generation in zebrafish. Three structurally related compounds (Cardionogen-1 to Cardionogen-3) identified from our screen enlarge the size of the developing heart via myocardial hyperplasia. Increased cardiomyocyte number in Cardionogen-treated embryos is due to expansion of cardiac progenitor cells. In zebrafish embryos and murine embryonic stem (ES) cells, Cardionogen treatment promotes cardiogenesis during and after gastrulation, whereas it inhibits heart formation before gastrulation. Cardionogen-induced effects can be antagonized by increasing Wnt/β-catenin signaling activity. We demonstrate that Cardionogen inhibits Wnt/β-catenin-dependent transcription in murine ES cells and zebrafish embryos. Cardionogen can rescue Wnt8-induced cardiomyocyte deficiency and heart-specific phenotypes during development. These findings demonstrate that in vivo small-molecule screens targeting heart size can reveal compounds with cardiomyogenic effects and identify underlying target pathways.