Discovering small molecules that promote cardiomyocyte generation by modulating Wnt signaling

Terri T. Ni; Eric J. Rellinger; Amrita Mukherjee; Shuying Xie; Lauren Stephens; Curtis A. Thorne; Kwangho Kim; Jiangyong Hu; Ethan Lee; Larry Marnett; Antonis K. Hatzopoulos; Tao P. Zhong

doi:10.1016/j.chembiol.2011.09.015

Discovering small molecules that promote cardiomyocyte generation by modulating Wnt signaling

Terri T. Ni
, Eric J. Rellinger
, Amrita Mukherjee
, Shuying Xie
, Lauren Stephens
, Curtis A. Thorne
, Kwangho Kim
, Jiangyong Hu
, Ethan Lee
, Larry Marnett
, Antonis K. Hatzopoulos
, Tao P. Zhong

Producción científica: Article › revisión exhaustiva

55 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	1658-1668
Número de páginas	11
Publicación	Chemistry and Biology
Volumen	18
N.º	12
DOI	https://doi.org/10.1016/j.chembiol.2011.09.015
Estado	Published - dic 23 2011

Nota bibliográfica

Funding Information:
We are indebted to John Guan for his invaluable assistance in fish care and Alex Waterson for his efforts in chemical synthesis. We thank Geoffrey Burns for cmlc2-EGFP and cmlc2-DsRed fish, Randall Moon for hsp-wnt8 fish, G.J. Robbins for providing Myh6 promoter plasmid, and P. ten Dijke for BRE 2 -Luc construct. We are grateful to Bruce Appel, Scott Baldwin, Wenbiao Chen, Josh Gamse, Daqing Jin, and members of our laboratories for comments on the manuscript and helpful discussions. This research is supported in part by grants NIH-NS064852 (T.P.Z.), HL083958 (A.K.H.), NIH-UL1RR024975 (VICTR), and Fudan University-EZH1322001 (T.P.Z.).

Financiación

We are indebted to John Guan for his invaluable assistance in fish care and Alex Waterson for his efforts in chemical synthesis. We thank Geoffrey Burns for cmlc2-EGFP and cmlc2-DsRed fish, Randall Moon for hsp-wnt8 fish, G.J. Robbins for providing Myh6 promoter plasmid, and P. ten Dijke for BRE 2 -Luc construct. We are grateful to Bruce Appel, Scott Baldwin, Wenbiao Chen, Josh Gamse, Daqing Jin, and members of our laboratories for comments on the manuscript and helpful discussions. This research is supported in part by grants NIH-NS064852 (T.P.Z.), HL083958 (A.K.H.), NIH-UL1RR024975 (VICTR), and Fudan University-EZH1322001 (T.P.Z.).

Financiadores	Número del financiador
Fudan University-EZH1322001
NIH-NS064852	HL083958, NIH-UL1RR024975
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	R21NS064852

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/j.chembiol.2011.09.015

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abstract = "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.",

author = "Ni, \{Terri T.\} and Rellinger, \{Eric J.\} and Amrita Mukherjee and Shuying Xie and Lauren Stephens and Thorne, \{Curtis A.\} and Kwangho Kim and Jiangyong Hu and Ethan Lee and Larry Marnett and Hatzopoulos, \{Antonis K.\} and Zhong, \{Tao P.\}",

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AU - Stephens, Lauren

AU - Thorne, Curtis A.

AU - Kim, Kwangho

AU - Hu, Jiangyong

AU - Lee, Ethan

AU - Marnett, Larry

AU - Hatzopoulos, Antonis K.

AU - Zhong, Tao P.

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Discovering small molecules that promote cardiomyocyte generation by modulating Wnt signaling

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

Acceder al documento

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Huella

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