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.

Figure 1

Structure and Homology of the Vertebrate GATA Proteins All GATA factors share a similar zinc finger DNA-binding domain, a feature that defines this family of transcription factors. The zinc finger (ZnF) region is also involved in protein interactions with cofactors and/or other transcriptional partners. Transactivation domains are located in the N-terminal (N-term) and C-terminal (C-term) regions. The percent homology among the different GATA proteins (as deduced from the mouse sequences) in the N-terminal, C-terminal, and zinc finger domains is indicated. NLS, Nuclear localization signal.

Figure 2

Expression of GATA Factors and Their FOG Cofactor Proteins during Gonadal and Adrenal Development Contribution of cells from adrenogenital primordium and neural crest cells ultimately give rise to the cortex and medulla of the mature adrenal gland. The testis and ovary develop from a bipotential gonad common to both sexes. GATA factors and FOG2 exhibit overlapping expression patterns throughout development of these three endocrine organs (see text for references). #, Expression specific to cells of the adrenal medulla; *, expression in germ cells.

Figure 3

Involvement of Intracellular Signaling Mechanisms in the Regulation of GATA4 Activity in Gonadal Cells In response to hormonal signals and/or growth factors, activation of the cAMP/PKA and MAPK signaling pathways leads to phosphorylation of GATA4 on specific serine residues: Ser261, a PKA target, and Ser105, a MAPK target. GATA4 phosphorylation increases its DNA-binding and transactivation properties on different gonadal promoters and enhances the ability of GATA4 to recruit and cooperate with different transcriptional partners such as SF-1 (NR5A1), liver receptor homolog 1 (LRH-1/NR5A2), CCAAT/enhancer-binding protein (C/EBPβ), and CBP. In murine and rat granulosa cells, signaling elicited by gonadotropins or TGFβ family members increases Gata4 transcription. TGFβ-mediated activation of Smad3 and its cooperation with GATA4 also leads to robust transcription of gonadal genes such as Inha (see text for references).