Role of the GATA Family of Transcription Factors in Endocrine Development, Function, and Disease

Abstract

The WGATAR motif is a common nucleotide sequence found in the transcriptional regulatory regions of numerous genes. In vertebrates, these motifs are bound by one of six factors (GATA1 to GATA6) that constitute the GATA family of transcriptional regulatory proteins. Although originally considered for their roles in hematopoietic cells and the heart, GATA factors are now known to be expressed in a wide variety of tissues where they act as critical regulators of cell-specific gene expression. This includes multiple endocrine organs such as the pituitary, pancreas, adrenals, and especially the gonads. Insights into the functional roles played by GATA factors in adult organ systems have been hampered by the early embryonic lethality associated with the different Gata-null mice. This is now being overcome with the generation of tissue-specific knockout models and other knockdown strategies. These approaches, together with the increasing number of human GATA-related pathologies have greatly broadened the scope of GATA-dependent genes and, importantly, have shown that GATA action is not necessarily limited to early development. This has been particularly evident in endocrine organs where GATA factors appear to contribute to the transcription of multiple hormone-encoding genes. This review provides an overview of the GATA family of transcription factors as they relate to endocrine function and disease.

GATA6 inactivating mutations are associated with heart defects and, inconsistently, with pancreatic agenesis and diabetes

“…Therefore, our results do not suggest a key role of GATA6 in the specific beta cell lineage, but these results would need further investigation as they are limited to gene expression analyses. In mice, in which GATA6 has been further studied, expression-based analyses suggest that GATA6 could play a role in very early pancreas specification [6][7][8]. Nevertheless, it has been reported that transgenic mouse embryos expressing a GATA6-engrailed dominant repressor fusion protein in the pancreatic epithelium and in islets revealed two distinct phenotypes, either pancreatic agenesis or a simple reduction in pancreatic tissue [6], implying a putative spectrum of phenotypes, as we noted in our Intra-uterine growth retardation…”

Loss-of-function mutation in GATA4 causes anomalies of human testicular development

“…However, GATA4 is expressed in the developing ovary as well as in adult granulosa and thecal cells (5), which suggests that either the p.Gly221Arg mutation specifically impairs testicular development or that ovarian development may be less sensitive than the testis to reduced GATA4 activity. siGata4 transgenic mice support the latter hypothesis, where the reduction of Gata4 expression in the testis is accompanied by a significant reduction of GATA4 downstream target genes.…”

The steroid receptor RNA activator protein is recruited to promoter regions and acts as a transcriptional repressor

“…Briefly, TF-array-I was incubated with 5 lg of recombinant SRAP protein (ProMab Biotechnologies Inc., Albany, CA) or without (control blot) for 2 h at room temperature. Immunodetection was performed using a primary anti-SRAP antibody (targeting aa [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] and chemiluminescence signals were captured and analyzed as described [6]. For both control and samples blots, intensity of the area (in counts/mm 2 ) encompassing the two spots corresponding to each transcription factor was first corrected by subtracting the signal of an immediately negative adjacent area (local background).…”

“…Beside steroid receptors, several other transcription factors such as FOS [27], GATA1 [32] and ETS1 [10], known to participate in critical normal developmental steps or to events underlying tumorigenesis, directly interact with SRAP (Table 1). It is of interest that an interaction has been observed between SRAP and HAND1, essential to heart development [13].…”