Glycogen synthase kinase 3α and 3β have distinct functions during cardiogenesis of zebrafish embryo

Huang Chieh Lee, Jen Ning Tsai, Pei Yin Liao, Wei Yuan Tsai, Kai Yen Lin, Chung Cheng Chuang, Chi Kuang Sun, Wen Chang Chang, Huai Jen Tsai

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Background. Glycogen synthase kinase 3 (GSK3) encodes a serine/threonine protein kinase, is known to play roles in many biological processes. Two closely related GSK3 isoforms encoded by distinct genes: GSK3α (51 kDa) and GSK3β (47 kDa). In previously studies, most GSK3 inhibitors are not only inhibiting GSK3, but are also affecting many other kinases. In addition, because of highly similarity in amino acid sequence between GSK3α and GSK3β, making it difficult to identify an inhibitor that can be selective against GSK3α or GSK3β. Thus, it is relatively difficult to address the functions of GSK3 isoforms during embryogenesis. At this study, we attempt to specifically inhibit either GSK3α or GSK3β and uncover the isoform-specific roles that GSK3 plays during cardiogenesis. Results. We blocked gsk3α and gsk3β translations by injection of morpholino antisense oligonucleotides (MO). Both gsk3α- and gsk3β-MO-injected embryos displayed similar morphological defects, with a thin, string-like shaped heart and pericardial edema at 72 hours post-fertilization. However, when detailed analysis of the gsk3α- and gsk3β-MO-induced heart defects, we found that the reduced number of cardiomyocytes in gsk3α morphants during the heart-ring stage was due to apoptosis. On the contrary, gsk3β morphants did not exhibit significant apoptosis in the cardiomyocytes, and the heart developed normally during the heart-ring stage. Later, however, the heart positioning was severely disrupted in gsk3β morphants. bmp4 expression in gsk3β morphants was up-regulated and disrupted the asymmetry pattern in the heart. The cardiac valve defects in gsk3β morphants were similar to those observed in axin1 and apcmcr mutants, suggesting that GSK3β might play a role in cardiac valve development through the Wnt/β-catenin pathway. Finally, the phenotypes of gsk3α mutant embryos cannot be rescued by gsk3β mRNA, and vice versa, demonstrating that GSK3α and GSK3β are not functionally redundant. Conclusion. We conclude that (1) GSK3α, but not GSK3β, is necessary in cardiomyocyte survival; (2) the GSK3β plays important roles in modulating the left-right asymmetry and affecting heart positioning; and (3) GSK3α and GSK3β play distinct roles during zebrafish cardiogenesis.

Original languageEnglish
Article number93
JournalBMC Developmental Biology
Volume7
DOIs
Publication statusPublished - Sep 28 2007
Externally publishedYes

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Glycogen Synthase Kinase 3
Zebrafish
Embryonic Structures
Morpholinos
Antisense Oligonucleotides
Cardiac Myocytes
Protein Isoforms
Heart Valves

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Lee, H. C., Tsai, J. N., Liao, P. Y., Tsai, W. Y., Lin, K. Y., Chuang, C. C., ... Tsai, H. J. (2007). Glycogen synthase kinase 3α and 3β have distinct functions during cardiogenesis of zebrafish embryo. BMC Developmental Biology, 7, [93]. https://doi.org/10.1186/1471-213X-7-93

Glycogen synthase kinase 3α and 3β have distinct functions during cardiogenesis of zebrafish embryo. / Lee, Huang Chieh; Tsai, Jen Ning; Liao, Pei Yin; Tsai, Wei Yuan; Lin, Kai Yen; Chuang, Chung Cheng; Sun, Chi Kuang; Chang, Wen Chang; Tsai, Huai Jen.

In: BMC Developmental Biology, Vol. 7, 93, 28.09.2007.

Research output: Contribution to journalArticle

Lee, Huang Chieh ; Tsai, Jen Ning ; Liao, Pei Yin ; Tsai, Wei Yuan ; Lin, Kai Yen ; Chuang, Chung Cheng ; Sun, Chi Kuang ; Chang, Wen Chang ; Tsai, Huai Jen. / Glycogen synthase kinase 3α and 3β have distinct functions during cardiogenesis of zebrafish embryo. In: BMC Developmental Biology. 2007 ; Vol. 7.
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abstract = "Background. Glycogen synthase kinase 3 (GSK3) encodes a serine/threonine protein kinase, is known to play roles in many biological processes. Two closely related GSK3 isoforms encoded by distinct genes: GSK3α (51 kDa) and GSK3β (47 kDa). In previously studies, most GSK3 inhibitors are not only inhibiting GSK3, but are also affecting many other kinases. In addition, because of highly similarity in amino acid sequence between GSK3α and GSK3β, making it difficult to identify an inhibitor that can be selective against GSK3α or GSK3β. Thus, it is relatively difficult to address the functions of GSK3 isoforms during embryogenesis. At this study, we attempt to specifically inhibit either GSK3α or GSK3β and uncover the isoform-specific roles that GSK3 plays during cardiogenesis. Results. We blocked gsk3α and gsk3β translations by injection of morpholino antisense oligonucleotides (MO). Both gsk3α- and gsk3β-MO-injected embryos displayed similar morphological defects, with a thin, string-like shaped heart and pericardial edema at 72 hours post-fertilization. However, when detailed analysis of the gsk3α- and gsk3β-MO-induced heart defects, we found that the reduced number of cardiomyocytes in gsk3α morphants during the heart-ring stage was due to apoptosis. On the contrary, gsk3β morphants did not exhibit significant apoptosis in the cardiomyocytes, and the heart developed normally during the heart-ring stage. Later, however, the heart positioning was severely disrupted in gsk3β morphants. bmp4 expression in gsk3β morphants was up-regulated and disrupted the asymmetry pattern in the heart. The cardiac valve defects in gsk3β morphants were similar to those observed in axin1 and apcmcr mutants, suggesting that GSK3β might play a role in cardiac valve development through the Wnt/β-catenin pathway. Finally, the phenotypes of gsk3α mutant embryos cannot be rescued by gsk3β mRNA, and vice versa, demonstrating that GSK3α and GSK3β are not functionally redundant. Conclusion. We conclude that (1) GSK3α, but not GSK3β, is necessary in cardiomyocyte survival; (2) the GSK3β plays important roles in modulating the left-right asymmetry and affecting heart positioning; and (3) GSK3α and GSK3β play distinct roles during zebrafish cardiogenesis.",
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AU - Lin, Kai Yen

AU - Chuang, Chung Cheng

AU - Sun, Chi Kuang

AU - Chang, Wen Chang

AU - Tsai, Huai Jen

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