Stanford Home
Ovarian Kaleidoscope Database (OKdb)

Home

History

Transgenic Mouse Models

INFORGRAPHICS

Search
Submit
Update
Chroms
Browse
Admin

Hsueh lab

HPMR

Visits
since 01/2001:
176557

GATA binding protein 6 OKDB#: 340
 Symbols: GATA6 Species: human
 Synonyms:  Locus: 18q11.1-q11.2 in Homo sapiens

For retrieval of Nucleotide and Amino Acid sequences please go to: OMIM Entrez Gene
Mammalian Reproductive Genetics   Endometrium Database Resource   Orthologous Genes   UCSC Genome Browser   GEO Profiles new!   Amazonia (transcriptome data) new!
R-L INTERACTIONS   MGI

DNA Microarrays
 SHOW DATA ...
link to BioGPS
General Comment GATA factors constitute a family of transcriptional regulatory proteins expressed with distinct developmental and tissue-specific profiles and thought to regulate cell-restricted programs of gene expression. Suzuki et al. (1996) described the molecular cloning, chromosomal location, and the transcription of the human GATA6 gene. The cDNA encodes a predicted 449-amino acid protein that is highly conserved among vertebrates and includes 2 adjacent zinc finger/basic domains characteristic of the GATA factor family. The gene is transcribed in a pattern overlapping that of GATA4. Transcripts for both of these genes are prominent in heart, pancreas, and ovary. Suzuki et al. (1996) commented that GATA6 is a prime candidate for a gene that regulates the differentiative state of vascular smooth muscle cells.
NCBI Summary: This gene is a member of a small family of zinc finger transcription factors that play an important role in the regulation of cellular differentiation and organogenesis during vertebrate development. This gene is expressed during early embryogenesis and localizes to endo- and mesodermally derived cells during later embryogenesis and thereby plays an important role in gut, lung, and heart development. Mutations in this gene are associated with several congenital defects. [provided by RefSeq, Mar 2012]
General function Nucleic acid binding, DNA binding, Transcription factor
Comment
Cellular localization Nuclear
Comment
Ovarian function Follicle development, Antral follicle growth, Luteinization
Comment The GATA-Keepers of Ovarian Development and Folliculogenesis. LaVoie HA 2014 et al. The transcription factors GATA4 and GATA6 are expressed in the embryonic and postnatal gonads and implicated as regulators of gonadal functions including steroidogenesis. The broad spatiotemporal expression and potentially overlapping functions of GATA factors complicates the task of defining all their roles. A role in embryonic development for both factors was indicated by early studies with genetically engineered mice lacking either Gata4 or Gata6, where homozygous deletion of either gene resulted in embryonic lethality. Gata4 null mice die between E8.5 and E10.5 with defects in ventral morphogenesis and cardiac development 3], and Gata6 null mice die between E6.5 and E7.5 with defects in endodermal differentiation [4]. The early studies with Gata null mice revealed little about the role of GATA4 or GATA6 in gonadal development and nothing about postnatal roles for these factors. Forced overexpression of GATA4 and GATA6 in cultured cells indicated that some gonadal gene promoters, such as that for Star and CYP19a1, could be driven efficiently by either factor [2]. In addition, RNAi-mediated depletion of GATA4, GATA6, and their combination in cultured ovarian granulosa cells revealed these GATA factors have both common and unique gene targets with combined GATA4 plus GATA6 depletion affecting a greater number of genes than with reduction of either factor alone [5]. Yet, it was not clear if the data from cell culture studies actually translated to the intact gonad or was relevant to developmental changes that occur as germ cells mature, such as during follicle maturation in the ovary, and thus more refined gene targeting animal studies were needed.Since the original creation of the Gata4 and Gata6 null mice several additional genetic approaches have been utilized to study mainly GATA4 in the developing or postnatal gonad in mice. These genetic approaches have included analyses of heterozygous mice, use of inducible Cre vectors with floxed Gata4 or Gata6 genes, Amhr2Cre targeting Gata deletions to ovarian somatic cells, and knock-in studies disrupting the interaction of GATA4 with cofactor FOG2 (recently reviewed in [6]). Each animal model had its limitations but each provided a piece of the puzzle regarding the role of GATA4 in gonadal development and function. GATA4 was found to be required for formation of the genital ridge of both sexes [7]. For the ovary, the common finding in most of these studies was that depletion of GATA4 results in abnormal responses to exogenous gonadotropins and impaired fertility in adults. Fewer studies addressed GATA6 function in the ovary. Only recently have the combined functions of GATA4 and GATA6 in ovarian follicular development and function been investigated using Cre vectors targeting ovarian somatic cells. Combined requirement for GATA4 and GATA6 in postnatal follicle maturation was confirmed in a recent study by Bennett et al. [8] who examined the individual and combined effects of GATA4 and GATA6 depletion in ovarian granulosa cells utilizing floxed Gata4 and Gata6 genes and Cre expression driven by the aromatase promoter (Cyp19Cre). Cyp19Cre is expressed in granulosa cells of all antral follicles with low or no expression in early follicles (primordial and primary) and no Cyp19Cre mediated recombination is observed before postnatal day 10 [9]. Cyp19Cre mediated depletion of GATA4 in granulosa cells resulted in a 75% decrease in litter size, whereas GATA6 depletion had no effect; however, the combined depletion of GATA4 and GATA6 resulted in complete infertility accompanied by the absence of large preovulatory follicles and corpora lutea [8]. Moreover, combined knockdown of GATA4 and GATA6 also resulted in elevated serum FSH and LH and decreased estradiol in proestrous animals. In sum, combined depletion of GATA4 and GATA6 in the postnatal mouse starting in the peripubertal period demonstrated that there is partial compensation of GATA4 loss by GATA6 in the granulosa cells of the follicle, and that loss of both factors impedes advanced follicular development and ovulation. As exciting as these findings were, the animal model did not allow the evaluation of GATA4 and GATA6 during fetal development or the early postnatal period.In a recent issue of Biology of Reproduction, Padua et al [10] have investigated the combined roles of GATA4 and GATA6 in fetal and early postnatal ovarian development in mice. The authors utilized Sf1Cre to create targeted Gata4/6 gene deletions within the somatic cells of the developing gonad. Sf1Cre expresses in the embryonic gonad somatic cells, adrenals, pituitary, and hypothalamus from mid-gestation onward [11], nonetheless the extragonadal expression of Sf1Cre is not expected to impact early ovarian development. Padua et al. showed that combined GATA4 and GATA6 reduction in the gonad initiated by Sf1Cre was robust by E13.5. Embryonic ovaries were evaluated at E13.5, E15.5 and E18.5, and postnatal days 4, 6, and 9 as animals survive two only weeks postnatally as they lack adrenals. In the fetus, combined loss of GATA4 and GATA6 decreased the expression of genes mediating the ovarian development pathway including Fst and Irx3 and pregranulosa and granulosa cell markers, SPPR2 and FOXL2, respectively. Normally follicle assembly in newborn mice occurs in the first few days of life with primordial follicles forming within 2-3 days after birth [12]. In Gata4/Gata6 conditional double mutant mice, a reduction in somatic cell proliferation was observed in all postnatal ovaries and an increase in apoptosis was measured at postnatal day 6, which coincided with smaller ovaries. At day 4, the wildtype ovary exhibited the expected primordial, primary, and multilayered preantral follicles. In contrast, the ovaries of animals with combined GATA4 and GATA6 depletion, exhibited only primordial follicles and many germ cells remained in clusters and had not recruited the pregranulosa somatic cells to form individual follicles. Another feature of the mutant ovary was that demarcation between the cortex and medullary regions was absent, consistent with a loss of follicle assembly and development. Remarkably, combined GATA4/6 depletion led to the loss of most oocytes in the postnatal ovary by day 9. Sf1Cre-mediated deletion of Gata4 alone showed a severe but incomplete block in follicular development with few follicles reaching the antral stage [13], and similar deletion of Gata6 exhibited normal ovarian structure and function [10], indicating that GATA4 can compensate for GATA6 depletion for much of early ovarian development. The data strongly argue that both GATA4 and GATA6 play a cooperative role in early ovarian development. Collectively, these recent studies show that the concerted efforts of GATA4 and GATA6 contribute to ovarian development during the embryonic stage (at E13.5 and beyond), postnatal follicle assembly and likely follicular maintenance, as well as maturation of the follicles to the preovulatory stage. An open question that remains for the ovary is 'What roles do these GATA factors play in the corpus luteum?' where GATA6 expression typically dominates. The answer awaits an appropriate conditional mutant mouse model which can maintain normal GATA expression through ovulation and deplete it in the new corpus luteum. ///////////////////////// [Ho et al reported increased Transcription and Increased mRNA Stability Contribute to Increased GATA6 mRNA Abundance in PCOS Theca Cells.
Expression regulated by FSH, LH
Comment Transcriptome analysis of FSH and FSH variant stimulation in granulosa cells from IVM patients reveals novel regulated genes. Perlman S et al. FSH is crucial for oocyte maturation and fertility and is the main component in infertility treatment in assisted reproduction. The granulosa cells expressing the FSH receptor interact with the oocyte and provide nourishing substrates controlling the oocyte maturation. Thus, transcriptome analysis of granulosa cells stimulated by FSH is of major importance in understanding the communication between oocytes and granulosa cells. In this study, gene expression profiles were assessed in human granulosa cells from normal cycling in vitro maturation (IVM) patients using oligonucleotide gene chips. Granulosa cells were stimulated for 2 h with either FSH or a previously generated glycosylated FSH variant (FSH1208) that exhibited increased in vivo activity because of prolonged half-life. The analysis identified 74 significantly FSH/FSH1208 regulated genes. Amongst these were well known FSH regulated genes as well as genes not previously described to be important in the FSH signalling pathway. These novel FSH regulated genes include transcription factors [cAMP responsive element modulator (CREM)/inducible cAMP early repressors (ICER), GATA 6, ZFN 361, Bcl11a, CITED1 and TCF 8] and other regulatory proteins and enzymes (IGF-BP3, syntaxin and PCK1) possibly important for oocyte/granulosa cell interaction and function. Array data were validated for 13 genes by northern blots or RT-PCR. Furthermore, no significant differences in gene regulation were detected between the two FSH analogs. This work uncovers novel data important for understanding the folliculogenesis. Furthermore, the results suggest that FSH1208 has a gene expression profile like FSH and thus, in the light of known prolonged in vivo activity, might be a candidate for improved infertility treatment.
Ovarian localization Granulosa, Theca, Luteal cells
Comment Transcription Factors GATA-4 and GATA-6: Molecular Characterization, Expression Patterns and Possible Functions during Goose (Anser cygnoides) Follicle Development. Yuan X 2014 et al. The transcription factors GATA-4 and GATA-6, members of the GATA family, play an important role in ovarian cell proliferation, differentiation and apoptosis. In this study, the full-length coding sequences of goose GATA-4 and GATA-6 were cloned and characterized. GATA-4 and GATA-6 consist of 1,236 and 1,104 nucleotides encoding proteins with 411 and 367 amino acids, respectively. The deduced amino acid sequences of both proteins include two adjacent zinc finger domains with the distinctive form (CVNC-X17-CNAC)-X29-(CANC-X17-CNAC) and share 84.76% identity within this domain. In silico prediction together with matching of the high affinity RRXS(T)Y motif revealed that the GATA-4 protein might be phosphorylated predominantly at S(233), but no phosphorylation site was found in the GATA-6 protein. Real-time quantitative PCR analysis showed that GATA-4 and GATA-6 mRNAs were co-expressed in goose follicles, moderately expressed in granulosa cells and weakly expressed in theca cells. The expression level of GATA-4 mRNA in healthy follicles was significantly higher than in atretic follicles or postovulatory follicles (P<0.01), and the expression level of GATA-6 mRNA in healthy follicles was significantly lower than in atretic follicles or postovulatory follicles (P<0.01). The expression level of GATA-4 mRNA in granulosa cells was downregulated during follicle development; the peak of expression occurred in the 8-10 mm follicles, and the lowest expression was in the F1 follicles. GATA-6 was upregulated and reached its peak expression in the F1 follicles. These results indicate that the molecular structural differences in goose GATA-4 and GATA-6 may be related to their different roles during follicle development. ///////////////////////// Laitinen MPE, et al 2000 reported that transcription factors GATA-4 and GATA-6 and a GATA family cofactor, FOG-2, are expressed in human ovary and sex cord-derived ovarian tumors. In rodents, GATA-4 is expressed in granulosa cells of primary and early antral follicles, whereas GATA-6 is expressed in granulosa cells of late antral follicles and luteal glands. Both transcription factors can be detected in lesser amounts in theca cells and interstitial cells. Based on in situ hybridization and immunohistochemistry that GATA-4 and GATA-6 messenger RNA (mRNA) and GATA-4 protein are present in granulosa and theca cells in both preantral and antral follicles. Both human ovarian tissue samples and freshly isolated granulosa luteal (GL) cells derived from preovulatory follicles of gonadotropin-treated women express GATA-4, GATA-6, and FOG-2 transcripts, and GATA-6 mRNA expression in GL cell cultures is stimulated by human CG and 8-bromo-cAMP. The findings support a role for GATA-binding proteins in human ovarian folliculogenesis. Moreover, these data suggest that GATA factors may contribute to the phenotypes of sex cord-derived ovarian tumors.
Follicle stages Antral, Preovulatory
Comment Wood JR, et al reported the molecular phenotype of polycystic ovary syndrome (PCOS) Theca cells and new candidate PCOS genes defined by microarray analysis. Polycystic ovary syndrome (PCOS) affects 5 percent of reproductive aged women and is the leading cause of anovulatory infertility. A hallmark of PCOS is excessive theca cell androgen secretion, which is directly linked to the symptoms of PCOS. However, the genes responsible for ovarian hyperandrogenemia of PCOS have not been identified. In this present study, the authors carried out microarray analysis to define the gene networks involved in excess androgen synthesis by the PCOS theca cells in order to identify candidate PCOS genes. PCOS theca cells have a gene expression profile that is distinct from normal theca cells. Included in the cohort of genes with increased mRNA abundance in PCOS theca cells were aldehyde dehydrogenase 6 and retinol dehydrogenase 2, which play a role in all-trans retinoic acid biosynthesis and the transcription factor GATA6. The authors demonstrated that retinoic acid and GATA6 increased the expression of 17a-hydroxylase providing a functional link between altered gene expression and intrinsic abnormalities in PCOS theca cells. Thus, the analyses have (1) defined a stable molecular phenotype of PCOS theca cells; (2) suggested new mechanisms for excess androgen synthesis by PCOS theca cells; and (3) identified new candidate genes that may be involved in the genetic etiology of PCOS.
Phenotypes
Mutations 1 mutations

Species: mouse
Mutation name:
type: null mutation
fertility: infertile - ovarian defect
Comment: GATA4 and GATA6 Knockdown During Luteinization Inhibits Progesterone Production and Gonadotropin Responsiveness in the Corpus Luteum of Female Mice. Convissar SM et al. (2015) The surge of luteinizing hormone triggers the genomic reprogramming, cell differentiation, and tissue remodeling of the ovulated follicle, leading to the formation of the corpus luteum. During this process, called luteinization, follicular granulosa cells begin expressing a new set of genes that allow the resulting luteal cells to survive in a vastly different hormonal environment and to produce the extremely high amounts of progesterone (P4) needed to sustain pregnancy. To better understand the molecular mechanisms involved in the regulation of luteal P4 production in vivo, the transcription factors GATA4 and GATA6 were knocked down in the corpus luteum by crossing mice carrying Gata4 and Gata6 floxed genes with mice carrying Cre recombinase fused to the progesterone receptor. This receptor is expressed exclusively in granulosa cells after the luteinizing hormone surge, leading to recombination of floxed genes during follicle luteinization. The findings demonstrated that GATA4 and GATA6 are essential for female fertility, whereas targeting either factor alone causes subfertility. When compared to control mice, serum P4 levels and luteal expression of key steroidogenic genes were significantly lower in conditional knockdown mice. The results also showed that GATA4 and GATA6 are required for the expression of the receptors for prolactin and luteinizing hormone, the main luteotropic hormones in mice. The findings demonstrate that GATA4 and GATA6 are crucial regulators of luteal steroidogenesis and are required for the normal response of luteal cells to luteotropins.//////////////////
Genomic Region show genomic region
Phenotypes and GWAS show phenotypes and GWAS
Links
OMIM (Online Mendelian Inheritance in Man: an excellent source of general gene description and genetic information.)
OMIM \ Animal Model
KEGG Pathways
Recent Publications
None
Search for Antibody

created: Dec. 11, 1999, midnight by: De   email:
home page:
last update: Oct. 30, 2015, 3:47 p.m. by: hsueh    email:



Use the back button of your browser to return to the Gene List.

Click here to return to gene search form