The Effects of the Expression of GATA Binding Protein 6 on Heart and Brain Development

Seo, Jungwon

doi:10.5352/JLS.2015.25.11.1230

Title & Authors

The Effects of the Expression of GATA Binding Protein 6 on Heart and Brain Development
Seo, Jungwon;

Abstract

GATA binding protein 6 (GATA6) is a transcription factor that is expressed in the early blastocyst stage and controls the expression of important genes in the differentiation and development of the heart, pancreas, and intestine. This study confirmed the role of GATA6 in cell differentiation and organ development using mouse embryonic stem cells and zebrafish, respectively. First, the mouse embryonic stem cells were differentiated into pacemaker cardiomyocytes. An RT-PCR analysis revealed that the expression of the GATA6 gene was greatly increased from day 4 of differentiation. The expression of GATA6 was upregulated prior to increased expression of NK2 homeobox 5 (Nkx2.5) and myocyte enhancer factor 2C (MEF2C), which are critical transcription factors involved in regulating heart formation. To examine the role of GATA6 in development, GATA6 morpholino was microinjected into zebrafish embryos. Knockdown of GATA6 expression significantly decreased the heart size and heart rate in the zebrafish compared to a control. In addition, the brains were degenerated in the GATA6 morpholino-injected zebrafish. Acridine orange staining showed that knockdown of GATA6 expression increased apoptotic cells in the brain. Interestingly, knockdown of GATA6 expression decreased apoptotic cells in the early bud stage. This study points to the importance of the GATA6 gene in heart and brain development.

Keywords

Brain;embryonic stem cells;GATA6;heart;zebrafish;

Language

Korean

Cited by

References

1.

Aronson, B. E., Stapleton, K. A. and Krasinski, S. D. 2014. Role of GATA factors in development, differentiation, and homeostasis of the small intestinal epithelium. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G474-490.

2.

Cai, W. S., Shen, F., Li, J. L., Feng, Z., Wang, Y. C., Xiao, H. Q. and Xu, B. 2014. Activated protease receptor-2 induces GATA6 expression to promote survival in irradiated colon cancer cells. Arch. Biochem. Biophys. 555-556, 28-32.

3.

Chao, C. S., McKnight, K. D., Cox, K. L., Chang, A. L., Kim, S. K. and Feldman, B. J. 2015. Novel GATA6 mutations in patients with pancreatic agenesis and congenital heart malformations. PLoS One 10, e0118449.

4.

Evans, M. J. and Kaufman, M. H. 1981. Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154-156.

5.

Gautier, E. L., Ivanov, S., Williams, J. W., Huang, S. C., Marcelin, G., Fairfax, K., Wang, P. L., Francis, J. S., Leone, P., Wilson, D. B., Artyomov, M. N., Pearce, E. J. and Randolph, G. J. 2014. Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival. J. Exp. Med. 211, 1525-1531.

6.

Hashem, S. I. and Claycomb, W. C. 2013. Genetic isolation of stem cell-derived pacemaker-nodal cardiac myocytes. Mol. Cell. Biochem. 383, 161-171.

7.

Kamnasaran, D. and Guha, A. 2005. Expression of GATA6 in the human and mouse central nervous system. Brain Res. Dev. Brain Res. 160, 90-95.

8.

Kamnasaran, D., Qian, B., Hawkins, C., Stanford, W. L. and Guha, A. 2007. GATA6 is an astrocytoma tumor suppressor gene identified by gene trapping of mouse glioma model. Proc. Natl. Acad. Sci. USA 104, 8053-8058.

9.

Keller, R. 2002. Shaping the vertebrate body plan by polarized embryonic cell movements. Science 298, 1950-1954.

10.

Kimmel, C. B., Ballard, W. W., Kimmel, S. R., Ullmann, B. and Schilling, T. F. 1995. Stages of embryonic development of the zebrafish. Dev. Dyn. 203, 253-310.

11.

Liu, F., Lu, M. M., Patel, N. N., Schillinger, K. J., Wang, T. and Patel, V. V. 2015. GATA-binding factor 6 contributes to atrioventricular node development and function. Circ. Cardiovasc. Genet. 8, 284-293.

12.

Lowry, J. A. and Atchley, W. R. 2000. Molecular evolution of the GATA family of transcription factors: conservation within the DNA-binding domain. J. Mol. Evol. 50, 103-115.

13.

MacRae, C. A. and Peterson, R. T. 2015. Zebrafish as tools for drug discovery. Nat. Rev. Drug Discov. 14, 721-731.

14.

Molkentin, J. D. 2000. The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression. J. Biol. Chem. 275, 38949-38952.

15.

Morgani, S. M. and Brickman, J. M. 2015. LIF supports primitive endoderm expansion during pre-implantation development development. Development doi: 10.1242/dev.125021.

16.

Morrisey, E. E., Tang, Z., Sigrist, K., Lu, M. M., Jiang, F., Ip, H. S. and Parmacek, M. S. 1998. GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. Genes Dev. 12, 3579-3590.

17.

Park, J. S., Kim, H. S., Kim, J. D., Seo, J., Chung, K. S., Lee, H. S., Huh, T. L., Jo, I. and Kim, Y. O. 2009. Isolation of a ventricle-specific promoter for the zebrafish ventricular myosin heavy chain (vmhc) gene and its regulation by GATA factors during embryonic heart development. Dev. Dyn. 238, 1574-1581.

18.

Patient, R. K. and McGhee, J. D. 2002. The GATA family (vertebrates and invertebrates). Curr. Opin. Genet. Dev. 12, 416-422.

19.

Shimizu, N., Watanabe, H., Kubota, J., Wu, J., Saito, R., Yokoi, T., Era, T., Iwatsubo, T., Watanabe, T., Nishina, S., Azuma, N., Katada, T. and Nishina, H. 2009. Pax6-5a promotes neuronal differentiation of murine embryonic stem cells. Biol. Pharm. Bull. 32, 999-1003.

20.

Westerfield, M. 1994. The Zebrafish Book : A Guide for the Laboratory Use of Zebrafish. Institute of Neuroscience. Eugene, OR: University of Oregon.

21.

Wu, J., Kubota, J., Hirayama, J., Nagai, Y., Nishina, S., Yokoi, T., Asaoka, Y., Seo, J., Shimizu, N., Kajiho, H., Watanabe, T., Azuma, N., Katada, T. and Nishina, H. 2010. p38 Mitogen-activated protein kinase controls a switch between cardiomyocyte and neuronal commitment of murine embryonic stem cells by activating myocyte enhancer factor 2C-dependent bone morphogenetic protein 2 transcription. Stem Cells Dev. 19, 1723-1734.

22.

Xin, M., Davis, C. A., Molkentin, J. D., Lien, C. L., Duncan, S. A., Richardson, J. A. and Olson, E. N. 2006. A threshold of GATA4 and GATA6 expression is required for cardiovascular development. Proc. Natl. Acad. Sci. USA 103, 11189-11194.