American Journal of Medical and Biological Research
ISSN (Print): 2328-4080 ISSN (Online): 2328-4099 Website: Editor-in-chief: Apply for this position
Open Access
Journal Browser
American Journal of Medical and Biological Research. 2020, 8(1), 17-23
DOI: 10.12691/ajmbr-8-1-3
Open AccessCase Report

The Atypical Expression of Retinoic Acid Inducible GATA6 Protein in Placenta is a Convenient Biomarker for Newborn Health Assessment

Abel Kangnidé1, Denis Akpovo2 and Callinice D. Capo-Chichi1,

1Department of Biochemistry and Cell Biology; Division of Molecular Biomarker in Cancer and Nutrition (BMCN); Institute of Biomedical Sciences and Applications (ISBA); Faculty of Sciences and Technics (FAST); University of Abomey Calavi (UAC), Cotonou, Benin

2Zonal Hospital SURU-LERE, Department of gynecology/obstetrics, Cotonou, Benin

Pub. Date: November 12, 2020

Cite this paper:
Abel Kangnidé, Denis Akpovo and Callinice D. Capo-Chichi. The Atypical Expression of Retinoic Acid Inducible GATA6 Protein in Placenta is a Convenient Biomarker for Newborn Health Assessment. American Journal of Medical and Biological Research. 2020; 8(1):17-23. doi: 10.12691/ajmbr-8-1-3


Background: Embryonic health assessment prior to delivery is not a priority in Africa due to the lack of efficient platforms for biomarker screening of defective heart or metabolic syndromes. Beside genetic mutations, some environmental, nutritional, or epigenetic events can induce abnormal protein expression impacting embryonic heart and gut developments. Among these proteins is the retinoic acid (vitamin A) inducible GATA6 which acts as transcription factor targeting the promoter of gene stimulated during placenta, embryonic heart and gut lineage specification. The objective of this study is to investigate GATA6 expression profile in placenta cells, to determine the impact of its abnormal expression on the newborn survival. Methods: Ethical approval of CER-ISBA) was obtained prior to placenta sample collection in the hospital obstetric service. Micro-fragments of placenta tissues (n=80) were collected after delivery and lysed for GATA6 analysis with immunoblot (western blot) method. Results: We observed two isoforms of GATA6 (long L and short S isoforms). All placenta lysates of living newborn expressed the type S isoform of GATA6 (n=76). In all 80 samples there is variable expression frequency for the type L isoform of GATA6. Normal expression of Type L isoform of GATA6 was observed in 63.8% of the samples; overexpression was observed in 7.5% of the samples; low expression was in 20% of them and totally lost in 8.7% of the samples. Retrospective analysis of 6 stillborn infant charts, linked 4 of them to deficient placental GATA6. Conclusion: Our preliminary data suggested that GATA6 could be used as biomarker for embryonic and newborn survival prognostic as well as for the postnatal screening of the risk to develop congenital heart diseases and metabolic syndromes during lifespan.

GATA6 isoform L biomarker congenital deficiency heart defect metabolic syndrome stillborn

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit


[1]  Sun C, Denisenko O, Sheth B, Cox A, Lucas ES, Smyth NR, and Fleming TP. Epigenetic regulation of histone modifications and Gata6 gene expression induced by maternal diet in mouse embryoid bodies in a model of developmental programming. BMC Dev Biol, 2015; 15: 3.
[2]  Fleming TP, Kwong WY, Porter R, Ursell E, Fesenko I, Wilkins A, Miller DJ, Watkins AJ, Eckert JJ. The embryo and its future. Biol Reprod. 2004 Oct; 71(4): 1046-54.
[3]  Steegers-Theunissen RPM, Twigt J, Pestinger V, Kevin D Sinclair KD. The periconceptional period, reproduction and long-term health of offspring: the importance of one-carbon metabolism. Hum Reprod Update, Nov-Dec 2013; 19(6): 640-55.
[4]  Barker DJ. The origins of the developmental origins theory. J Intern Med. 2007 May; 261(5): 412-7.
[5]  Barker DJ, Thornburg KL. The obstetric origins of health for a lifetime. Clin Obstet Gynecol. 2013; 56(3): 511-9.
[6]  Suzuki E1, Evans T, Lowry J, Truong L, Bell DW, Testa JR, Walsh K. The human GATA-6 gene: structure, chromosomal location, and regulation of expression by tissue-specific and mitogen-responsive signals. 1996 Dec 15; 38(3): 283-90.
[7]  Cai KQ, Capo-Chichi CD, Rula ME, Yang DH, Xu XX. Dynamic GATA6 expression in primitive endoderm formation and maturation in early mouse embryogenesis. Dev Dyn. 2008; 237(10): 2820-9.
[8]  Capo-chichi CD, Alladagbin JD, Brun L, Aguida B, Agossou KV, Anagbla T, Salmane A, Xu XX. Sanni A. Deficiency of GATA6 as a Molecular Tool to Assess the Risk for Cervical Cancer. American Journal of Biomedical Research. 2014, 2(1), 1-6.
[9]  Xin M, Davis CA, Molkentin JD, Lien CL, Duncan SA, Richardson JA, Olson EN. A threshold of gata4 and gata6 expression is required for cardiovascular development. Proc Natl Acad Sci USA. 2006; 103:11189-11194.
[10]  Meng Y, Moore R, Tao W, Smith ER, Tse JD, Caslini C, Xu XX. GATA6 phosphorylation by Erk1/2 propels exit from pluripotency and commitment to primitive endoderm. Dev Biol. 2018 Apr 1; 436(1): 55-65.
[11]  Wang Y, Smedberg JL, Cai KQ, Capo-Chichi DC, Xu XX. Ectopic expression of GATA6 bypasses requirement for Grb2 in primitive endoderm formation. Dev Dyn. 2011 Mar; 240(3): 566-76.
[12]  Lipka A, Paukszto L, Majewska M, Jastrzebski JP, Myszczynski K, Panasiewicz G, Szafranska B. Identification of differentially expressed placental transcripts during multiple gestations in the Eurasian beaver (Castor fiber L.). Reprod Fertil Dev. 2017 Sep; 29(10): 2073-2084.
[13]  Yu L, Bennett JT, Wynn J, Carvill GL, Cheung YH, Shen Y, Mychaliska GB, Azarow KS, Crombleholme TM, Chung DH, Potoka D, Warner BW, Bucher B, Lim FY, Pietsch J, Stolar C, Aspelund G, Arkovitz MS; University of Washington Center for Mendelian Genomics, Mefford H, Chung W. Whole exome sequencing identifies de novo mutations in GATA6 associated with congenital diaphragmatic hernia. J Med Genet. 2014; 51(3): 197-202.
[14]  De Franco E, Shaw-Smith C, Flanagan SE, Shepherd MH, International NDM Consortium; Hattersley AT, Ellard S. GATA6 mutations cause a broad phenotypic spectrum of diabetes from pancreatic agenesis to adult-onset diabetes without exocrine insufficiency. Diabete, 2013; 62(3): 993-7.
[15]  Allen HL, Flanagan SE, Shaw-Smith C, De Franco E, Akerman I, Caswell R; International Pancreatic Agenesis Consortium, Ferrer J, Hattersley AT, Ellard S. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat Genet, 2011; 44(1): 20-2.
[16]  16. Perez-Garcia V, Fineberg E, Wilson R, Murray A, Mazzeo C, Tudor C, Sienerth A, White JK, Tuck E, Ryder EJ, Gleeson D, Siragher E, Wardle-Jones H, Staudt N, Wali N, Collins J, Geyer S, Busch-Nentwich EM, Galli A, Smith JC, Robertson E, Adams DJ, Weninger WJ, Mohun T, Hemberger M. Placentation defects are highly prevalent in embryonic lethal mouse mutants. Nature. 2018 Mar 22; 555(7697): 463-468.
[17]  Coan PM, Vaughan OR, McCarthy J, Mactier C, Burton GJ, Constância M, Fowden AL. Dietary composition programmes placental phenotype in mice. J Physiol. 2011 Jul 15;589(Pt 14): 3659-70.
[18]  Capo-chichi CD, Aguida B, Qi KC, Offrin G, Agossou VK, Sanni A, Xu XX. The Deficiency of Nuclear Proteins GATA6 and Lamin A/C as Prognostic Factor for Cervical Neoplasia. American Journal of Cancer Prevention, 2015, Vol. 3, No. 6, 109-116.
[19]  Xin M, Davis CA, Molkentin JD†, Lien CL, Duncan SA‡, James A. Richardson JA, Eric N. Olson EN. A threshold of GATA4 and GATA6 expression is required for cardiovascular development. Proc Natl Acad Sci U S A. 2006; 103(30): 11189-94.
[20]  Prendiville TW, Guo H, Lin Z, Zhou P, Stevens SM, He A, et al. Novel Roles of GATA4/6 in the Postnatal Heart Identified through Temporally Controlled, Cardiomyocyte-Specific Gene Inactivation by Adeno-Associated Virus Delivery of Cre Recombinase. PLoS One . 2015 May 29; 10(5): e0128105.
[21]  van Berlo JH, Elrod JW, van den Hoogenhof MM, York AJ, Aronow BJ, Duncan SA, Molkentin JD. The transcription factor GATA-6 regulates pathological cardiac hypertrophy. Circ Res. 2010 Oct 15; 107(8): 1032-40.
[22]  Liang Q, De Windt LJ, Witt SA, Kimball TR, Markham BE, Molkentin JD. The transcription factors gata4 and gata6 regulate cardiomyocyte hypertrophy in vitro and in vivo. J Biol Chem. 2001; 276: 30245-53.
[23]  Whitcomb J, Gharibeh L, Nemer M. From embryogenesis to adulthood: Critical role for GATA factors in heart development and function. IUBMB Life. 2020; 72(1): 53-67.
[24]  Suzuki S 1 , Nakao A , AR de Sarhat , A Furuya , K Matsuo , Y Tanahashi, Kajino H, Azuma H. A case of pancreatic agenesis and congenital heart defects with a novel GATA6 nonsense mutation: evidence of haploinsufficiency due to nonsense-mediated mRNA decay. Am J Med Genet A. 2014; 164A(2): 476-9.
[25]  Capo-Chichi CD, Smedberg JL, Rula M, Nicolas E, Yeung AT, Adamo RF, Frolov A, Godwin AK, Xu XX. Alteration of Differentiation Potentials by Modulating GATA Transcription Factors in Murine Embryonic Stem Cells. Stem Cells Int. 2010 May 11; 2010: 602068.
[26]  Xin, M., Davis, C.A., Molkentin, J.D., Lien, C.L., Duncan, S.A., Richardson, J.A., Olson, E.N., 2006. A threshold of gata4 and gata6 expression is required for cardiovascular development. Proc Natl Acad Sci U S A 103 (30), 11189-94.
[27]  Tiyaboonchai, A., Cardenas-Diaz, F. L., Ying, L., Maguire, J. A., Sim, X., Jobaliya, C.,Gagne, A. L., Kishore, S., Stanescu, D. E., Hughes, N. et al.(2017). GATA6 Plays an Important Role in the Induction of Human Definitive Endoderm, Development of the Pancreas, and Functionality of Pancreatic β Cells. Stem Cell Reports.
[28]  Villamayor L, Rodríguez-Seguel E, Araujo R, Carrasco M, Bru-Tarí E, Mellado-Gil JM, Gauthier BR,, Martinelli P, Quesada I, Soria B, Martín F, Cano DA, Rojas A. Diabetes, 2018; 67(3): 448-460.
[29]  Morrisey EE, Tang Z, Sigrist, K, Lu MM, Jiang F, Ip HS, Parmacek MS. GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo Genes Dev . 1998 Nov 15; 12(22): 3579-90.
[30]  Thompson CA, DeLaForest A, Battle MA. Patterning the gastrointestinal epithelium to confer regional-specific functions. Dev Biol. 2018 Mar 15; 435(2): 97-108.
[31]  Simon C. Langley-Evans Sarah McMullen. Developmental Origins of Adult Disease .Med Princ Pract 2010; 19: 87-98.
[32]  Tucker NR, Mahida S, Ye J, Abraham EJ, Mina JA, Parsons VA, McLellan MA, Shea MA, Hanley A, Benjamin EJ, Milan DJ, Lin H, Ellinor PT. Gain-of-function mutations in GATA6 lead to atrial fibrillation. Heart Rhythm 2017; 14(2): 284-291.
[33]  Li C, Li X, Pang S, Chen W, Qin X, Huang W, Zeng C, Yan B, Novel and Functional DNA Sequence Variants within the GATA6 Gene Promoter in Ventricular Septal Defects. Int. J. Mol. Sci. 2014, 15, 12677-12687.
[34]  Kodo K, Nishizawa T, Furutani M, Arai S, Yamamura E, Joo K, Takahashi T, Matsuoka R, Yamagishi H. GATA6 mutations cause human cardiac outflow tract defects by disrupting semaphorin-plexin signaling. Proc Natl Acad Sci U S A. 2009 Aug 18; 106(33): 13933-8.
[35]  Zhao R, Watt AJ, Li J, Luebke-Wheeler J, Morrisey EE, Duncan SA. GATA6 is essential for embryonic development of the liver but dispensable for early heart formation. Mol Cell Biol 2005 Apr; 25(7): 2622-31.