Disease relevance of Gata6

• The defects in G6-Nkx DH embryos and mice are similar to those observed in human neonates with respiratory distress syndromes, including bronchopulmonary dysplasia, and differential gene expression analysis reveals essential developmental pathways requiring synergistic regulation by both Gata6 and Titf1 (Nkx2.1) [1].
• Sox7 plays crucial roles in parietal endoderm differentiation in F9 embryonal carcinoma cells through regulating Gata-4 and Gata-6 expression [2].
• Overexpression of either GATA4 or GATA6 was sufficient to induce cardiomyocyte hypertrophy characterized by enhanced sarcomeric organization, a greater than 2-fold increase in cell surface area, and a significant increase in total protein accumulation [3].
• In the present work, GATA-6 mRNA was detected in adult mouse lung, purified mouse type II epithelial cells, and differentiated mouse pulmonary adenocarcinoma cells (MLE-15 cells), being co-expressed with TTF-1 mRNA [4].
• To model the increase in endogenous GATA4 and GATA6 transcriptional activity that occurs in response to hypertrophic stimulation, each factor was overexpressed in cardiomyocytes using recombinant adenovirus [3].

High impact information on Gata6

• GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo [5].
• GATA6 belongs to a family of zinc finger transcription factors that play important roles in transducing nuclear events that regulate cellular differentiation and embryonic morphogenesis in vertebrate species [5].
• In addition, these data demonstrate that GATA6 is required for establishment of the endodermally derived bronchial epithelium [5].
• Finally, to examine the function of GATA6 during later embryonic development, GATA6(-/-)-C57BL/6 chimeric mice were generated. lacZ-tagged GATA6(-/-) ES cells contributed to all embryonic tissues with the exception of the endodermally derived bronchial epithelium [5].
• These findings reveal a threshold of GATA4 and GATA6 activity that is required for gene expression in the developing cardiovascular system and underscore the potential of recessive mutations to perturb the delicate regulation of cardiovascular development [6].

Biological context of Gata6

• Gata4, Gata5, and Gata6 represent a subfamily of zinc-finger transcriptional regulators that are important in the development and differentiation of numerous tissues, including many endodermally-derived organs [7].
• At e17.5, transgenic Gata6-Engrailed embryos exhibit two distinct phenotypes: a complete absence of pancreas or a reduction in pancreatic tissue [7].
• Using backcross analysis, the Gata6 gene was localized to mouse chromosome 18, linked to the gene encoding transthyretin [8].
• In human ES cells, Oct-4 knockdown also induced morphological differentiation coincident with the upregulation of Gata6 [9].
• The transcription factor GATA6 is essential for branching morphogenesis and epithelial cell differentiation during fetal pulmonary development [10].

Anatomical context of Gata6

• We show that Gata6 mRNA is expressed predominantly in the developing pulmonary endoderm and epithelium, but at E15.5 also in the pulmonary mesenchyme [10].
• It is also expressed in early bronchial epithelium and the observation that this tissue does not receive any contribution from Gata6 double mutant embryonic stem (ES) cells in chimeric mice suggests that GATA6 may play a crucial role in lung development [10].
• A central feature of this altered cellular identity is the switch from predominant expression of Gata6 (endogenous to the adrenal cortex) to Gata4, which defines cellular identity in the ovary [11].
• Of the two genes, however, only Gata6 was expressed in vascular smooth muscle [8].
• Cotransfection experiments demonstrate that the human Dab2 promoter can be transactivated by forced expression of GATA-6 in NIH-3T3 cells [12].

Associations of Gata6 with chemical compounds

• We analyzed the in vitro differentiation of mouse embryonic stem cells deficient of GATA factors and conclude that GATA-4 is required for ES cells to perceive a cell positioning (cell aggregation) signal and GATA-6 is required to sense morphogenic (retinoic acid) signal [13].
• The GATA-6 and -4 proteins share high-level amino acid sequence identity over a proline-rich region at the amino terminus of the protein that is not conserved in other GATA family members [14].
• We have shown previously that mammalian GATA-6 genes have the potential to encode two protein isoforms, resulting from alternative, in-frame, initiator methionine codons [15].
• Finally, Western blot analysis showed GATA-4 and GATA-6 proteins in DEX but not control nuclear extracts [16].
• Expression of GATA-6-engrailed was initiated at embryonic day (E) 6-7 by treatment of the dam with doxycycline [17].

Physical interactions of Gata6

• Electrophoretic mobility shift assays (EMSAs) indicate that the putative CRE and GATA sites indeed bind cAMP response element modulator 1/c-Jun and the GATA6 protein, respectively [18].
• The GATA6 cardiac enhancer contained a binding site for Nkx2.5 that was essential for cardiac-specific expression in transgenic mice [19].
• Gel mobility shift assays demonstrate that GATA-6 binds to a consensus site adjacent to the CArG box in the telokin promoter [20].
• Codon 12 region of mouse K-ras gene is the site for in vitro binding of transcription factors GATA-6 and NF-Y [21].

Regulatory relationships of Gata6

• Transgenic mice expressing Gata6 cDNA under the control of the human Surfactant Protein-C (SP-C) promoter were generated and their lungs were analyzed during fetal stages [22].
• Surprisingly, the specificity of GATA-6-induced transactivation of the Dab2 promoter is not mediated through its zinc finger DNA-binding domain [12].
• Finally, a functional role for GATA factor function in alveolar epithelial type 1 cell gene regulation is supported by the ability of GATA6 to trans-activate the mouse aquaporin-5 promoter [23].
• Using the P19-CL6 embryonal carcinoma (EC) cell line as an in vitro model of cardiogenesis, we show that GATA6 is the most abundantly expressed of the GATA factors in presumptive cardiac cells [24].
• This analysis revealed that GATA-6 strongly repressed telokin promoter activity [20].

Other interactions of Gata6

• Chimeras generated in a ROSA26 background show that endodermal cells in these abnormally branched areas are derived from Gata6 mutant ES cells, implicating that the defect is intrinsic to the endoderm [10].
• In addition, we show Gata6, but not Gata4, physically interacts with Nkx2.2, an essential islet transcription factor [7].
• RNase protection analysis showed that Gata6 is abundantly expressed in the heart, stomach, intestine, and ovaries of the adult mouse [8].
• Taken together, these data demonstrate that the mitogen-responsive phosphoprotein Dab2 is a downstream target of GATA-6 in the visceral endoderm [12].
• Taken together these results indicate that GATA-4 is not essential for terminal differentiation of cardiomyocytes and suggest that additional GATA-binding proteins known to be in cardiac tissue, such as GATA-5 or GATA-6, may compensate for a lack of GATA-4 [25].

Analytical, diagnostic and therapeutic context of Gata6

• The developmental expression patterns of Gata6 and the closely related gene Gata4 were directly compared using in situ hybridization [8].
• Gene targeting studies have demonstrated that the zinc finger transcription factor GATA-6 lies upstream in a transcriptional cascade that controls differentiation of the visceral endoderm [12].
• Comparison of these cell lines by microarray analysis identified GATA4 and GATA6 as differentially expressed genes [26].
• Based on these findings we studied GATA-4 and GATA-6 expression in 39 human adrenocortical tumors using RT-PCR, Northern analysis and immunohistochemistry [27].

References