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Molecular Endocrinology 22(4):781–798
Copyright © 2008 by The Endocrine Society
doi: 10.1210/me.2007-0513
MINIREVIEW
Role of the GATA Family of Transcription Factors in
Endocrine Development, Function, and Disease
Robert S. Viger, Séverine Mazaud Guittot, Mikko Anttonen, David B. Wilson, and
Markku Heikinheimo
Ontogeny-Reproduction Research Unit (R.S.V., S.M.G.), CHUQ Research Centre, Quebec City,
Canada G1V 4G2; Centre de Recherche en Biologie de la Reproduction (R.S.V.), Department of
Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Quebec City, Canada G1V 0A6;
Department of Obstetrics and Gynecology and Women’s Health Research Program (M.A.) and
Children’s Hospital and Women’s Health Research Program (M.H.), Biomedicum Helsinki, University
of Helsinki, FI-00014 Helsinki, Finland; and Department of Pediatrics (D.B.W., M.H.), Washington
University and St. Louis Children’s Hospital, St. Louis, Missouri 63110
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. (Molecular Endocrinology 22:
781–798, 2008)
G
the development of T lymphocytes (1). Their expression, however, is not limited to hematopoietic cells but
is also present in the brain, spinal cord, and inner ear
where they play important roles in the development of
these structures (2–4). In contrast, the GATA4/5/6 proteins are mainly found in tissues of mesodermal and
endodermal origin such as the heart, gut, and gonads
(5). Disruption of the Gata4 and Gata6 genes in mice
results in early embryo lethality due to defects in heart
tube formation and extraembryonic endoderm development, respectively (6–9). Although loss of GATA5
function is not lethal, female Gata5-null mice exhibit
genitourinary abnormalities (10). The physiological requirement for GATA function in humans is further supported by the more recent identification of GATA gene
mutations associated with human diseases, such as
dyserythropoietic anemia and thrombocytopenia
(GATA1 mutation); hypoparathyroidism, deafness, and
renal dysplasia (HDR syndrome; GATA3 mutation);
and congenital heart defects (GATA4 mutation)
(11–13).
ATA FACTORS ARE a group of evolutionarily
conserved transcriptional regulators that play
crucial roles in the development and differentiation of
all eukaryotic organisms. In vertebrates, the GATA
family comprises six members (named GATA1 to -6)
that can be separated into two subgroups based on
spatial and temporal expression patterns. GATA1/2/3
are expressed in hematopoietic cell lineages and are
essential for erythroid and megakaryocyte differentiation, the proliferation of hematopoietic stem cells, and
First Published Online January 3, 2008
Abbreviations: AMH, Anti-Müllerian hormone; CBP, CREBbinding protein; CRE, cAMP response element; CREB, CREbinding protein; e13.5, embryonic d 13.5; FOG, Friend of
GATA; GCT, granulosa cell tumor; GLP1, GATA-like protein
1; ␣GSU, ␣-glycoprotein subunit; LOH, loss of heterozygosity; PCOS, polycystic ovary syndrome; PKA, protein kinase A;
SF-1, steroidogenic factor 1.
Molecular Endocrinology is published monthly by The
Endocrine Society (http://www.endo-society.org), the
foremost professional society serving the endocrine
community.
781
782
Mol Endocrinol, April 2008, 22(4):781–798
All vertebrate GATA proteins contain a conserved
DNA-binding domain composed of two multifunctional
zinc fingers involved in DNA-binding and protein-protein interaction with other transcriptional partners
and/or cofactors (Fig. 1). Because members of the
GATA family share a highly conserved DNA-binding
domain, there is an apparent redundancy in DNA binding properties to target GATA sequences (14, 15).
These in vitro properties contrast, however, with their
often nonredundant roles in vivo (6, 7, 9, 16–18). The
specificity of GATA action is governed, in part, through
protein-protein interactions with other transcriptional
partners. Indeed, there is now an extensive list of
ubiquitously expressed or cell-restricted factors that
are known to cooperate with GATA factors to control
tissue-specific transcription in the hematopoietic system, the heart, and many other tissues (19–45). The
activity of GATA factors has also been shown to be
modulated by posttranslational modifications such as
sumoylation, acetylation, and phosphorylation. The effect of these modifications most often involves enhanced transcriptional activity due to changes in
GATA nuclear localization, DNA-binding, protein stability, and/or cofactor recruitment (see Table 1 for references). With respect to endocrine cells, GATA4
phosphorylation has been the best studied posttranslational modification to date (described further below).
Although originally classified as markers of hematopoietic and cardiac cells, the expression pattern and
functions attributed to GATA factors extend well beyond these cell lineages. Interestingly, GATA factors
have been described in most, if not all, of the endocrine organs where they are emerging as important
regulators of numerous genes coding for hormones or
proteins/enzymes involved in hormone biosynthesis. A
comprehensive list of putative GATA-regulated genes
Fig. 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.
Viger et al. • Minireview
in endocrine tissues is presented in Table 2. In the
sections that follow, our current understanding of the
expression and role of GATA factors in different endocrine organs is presented.
GATA FACTORS IN ENDOCRINE TISSUES
Hypothalamus and Pituitary
The expression of Gata4 in migrating GnRH neurons at
embryonic d 13.5 (e13.5) but not in mature GnRHsecreting neurons in mouse has led to the hypothesis
that GATA factors could play a role in the differentiation of the small population of neurosecretory cells
that mediate central nervous system control of reproduction (46). In hypothalamic neuronal GT1-7 cells,
GATA4 activates GnRH (Gnrh1) transcription through
binding to two GATA motifs arranged in tandem repeat
within the GnRH neuron-specific enhancer (46). Because the GATA-binding site is also involved in Gnrh1
gene regulation in the mature hypothalamus, the role
for GATA in Gnrh1 expression would not appear to be
limited to cell differentiation. The absence of GATA4
binding activity in adult hypothalamus nuclear extracts
does not exclude the possibility of the binding of another, yet to be identified, GATA family member or
some other transcriptional regulator (46).
The mature pituitary gland orchestrates the homeostasis of key endocrine organs by regulating their
function in response to signals coming from brain and
the periphery. Among the six adult differentiated hormone-secreting cell types, both thyrotrope and gonadotrope cells express GATA2 from e10.5 onward,
whereas GATA3 is transiently expressed during development (47). The secretory products of thyrotrope and
gonadotrope cells are heterodimers that share a common ␣-glycoprotein subunit (␣GSU) and a specific
␤-subunit (FSH␤, LH␤, and thyrotropin-␤). Interestingly, genes encoding ␣GSU (Cga) and thyrotropin-␤
(Tshb) are GATA2 target genes (21, 48, 49). Moreover,
although a functional GATA binding site has been described in the GnRH receptor promoter in pituitary
cells, the GATA factor that binds has not yet been
identified (50).
GATA2 is involved in both gonadotrope and thyrotrope terminal cell specification. The detailed analysis
of several transgenic mouse models such as expression of a dominant-negative form of GATA2 under the
control of Cga (␣GSU) regulatory sequences and overexpression of GATA2 directed by the Pou1f1 (Pit1)
promoter, have highlighted the complex mechanisms
whereby interactions between Pit1 and GATA2 contribute to pituitary cell fate determination (47, 51). In
gonadotropes where GATA2 is expressed in the absence of Pit1, GATA2 promotes the expression of
gonadotrope-specific genes. In thyrotropes, where
GATA2 and Pit1 are coexpressed, thyrotrope-specific
genes are up-regulated by the binding of both factors
to adjacent DNA cis-elements, whereas GATA motif-
Viger et al. • Minireview
Mol Endocrinol, April 2008, 22(4):781–798 783
Table 1. Posttranslational Modifications of GATA Factors
Modification
Sumoylation
Acetylation
Phosphorylation
GATA Protein
Species
GATA1
Mouse
K137
GATA2
Mouse
Not defined
GATA4
Mouse
K366
GATA1
Amino Acid(s)
Mouse/chicken Multiple:
K246, K252, K312 (major
sites)
GATA2
Human
Multiple
GATA3
Human
K305
GATA1
Mouse
GATA2
Mouse
S26, S49, S72, S162, S178,
S187, S310
MAPK-mediated
(Amino acid undefined)
Cdk-mediated (S227, T457)
PI-3K/Akt-dependent (S401)
Mouse
Human
GATA3
GATA4
Mouse
Human
Mouse
PKA-mediated (S308)
MAPK-mediated (undefined)
MAPK-mediated (S105)
PKA-mediated (S261)
containing gonadotrope-specific genes are down-regulated. This discrepancy comes from the ability of Pit1
to interact with a critical DNA-binding zinc finger of
GATA2, via its homeodomain, thus preventing GATA2
DNA-binding and target gene transactivation (47). Because of the early embryonic lethality of Gata2-null
mice resulting from severe anemia consistent with the
critical role of GATA2 in both primitive hematopoiesis
of the yolk sac and definitive hematopoiesis of the liver
(18), the role of GATA2 in later development was obscured. However, a recent study reporting pituitaryspecific Gata2 knockout mice has shed further light
into its role in pituitary function (52). Loss of GATA2 in
the anterior pituitary results in a decrease in gonadotrope and thyrotrope cell numbers at birth and a
marked decrease in secretory capacity of these cells in
the adult (52). Although Gata2 pituitary knockout mice
have defects in the same pituitary cell populations as
the dominant-negative GATA2 transgenic mice (47),
the extent of the defect is much less severe (52). This
difference has been proposed to be due to compensation by GATA3 that is up-regulated in the Gata2
pituitary knockout mice and that would normally be
targeted by the GATA2 dominant-negative. Thus,
GATA2 has been proposed to have a dual role in
pituitary function: the initial specification and/or proliferation of thyrotropes and the later maintenance of
hormone expression in mature thyrotropes and gonadotropes (52). Consistent with this hypothesis, GATA2
is found in most ␣GSU-positive and thyrotropin-secreting human pituitary adenomas (53).
Proposed Role(s)
Transcriptional repression
(sumoylation independent)
Transcriptional repression
(sumoylation independent)
Transcriptional activation,
nuclear localization
Transcriptional activation,
protein stability, DNAbinding, increased
functional activity
Transcriptional activation,
DNA-binding
Transcriptional activation,
increase functional activity
Protein stability
Undefined
Protein stability
Nuclear localization, DNAbinding
Transcriptional activation
Nuclear localization
Transcriptional activation,
DNA-binding, recruitment of
transcriptional partners
Refs.
200, 201
202
203, 204
205, 206
207
208
209, 210
211–213
214–216
112, 114, 118
Thyroid and Parathyroid
The parathyroid glands regulate calcium balance in the
body through the secretion and action of PTH. Developmentally, parathyroid glands, together with the thyroid, thymus, and ultimobranchial bodies, originate
from the pharyngeal region by the complex interactions between endoderm and neural crest derivatives
(54). GATA3 expression has been reported in human
embryos in the second and third branchial arches,
from which the parathyroids derive (55). Although a
consensus GATA binding site has been identified in
the proximal promoter of the murine PTH (Pth) gene
(56), its functional relevance remains unclear, and to
date, no other potential GATA3 target genes have
been identified in the developing parathyroid. Homozygous Gata3 knockout mice display mid-gestation
lethality (16), in part due to a noradrenaline deficiency
of the sympathetic nervous system, which can be
rescued by pharmacological treatment with catechol
intermediates (57). Because of this early embryonic
lethality, the generation of parathyroid-conditional
Gata3 transgenic mice would therefore be of particular
interest to gain insights into the role of GATA3 in adult
parathyroid gland physiology. However, the importance of GATA3 in parathyroid function has not come
from transgenic mice but rather from study of patients
suffering hypoparathyroidism, sensorineural deafness,
and renal anomaly (HDR) syndrome. HDR syndrome
has been linked to deletions or mutations of GATA3
that affect the integrity of its two zinc fingers (13,
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Mol Endocrinol, April 2008, 22(4):781–798
Viger et al. • Minireview
Table 2. Putative GATA Target Genes in Endocrine Tissues
Supporting
Evidence
Organ
Gene Name
Symbol
GATA Proteins
Hypothalamus
Pituitary
GnRH
Glycoprotein hormones, ␣-subunit
TSH, ␤-subunit
GnRH receptor
Anti-Müllerian hormone
Inhibin ␤-B
Doublesex and mab-3-related transcription factor 1
FSH receptor
Claudin 11
Testis-derived transcript
Coxsackie- and adenovirus receptor-like membrane protein
Sex-determining region Y chromosome
SRY-box containing gene 9
Inhibin ␣
Steroidogenic acute regulatory protein
P450 aromatase (via PII promoter)
17␣-Hydroxylase
P450 side chain cleavage
LH receptor
3␤-Hydroxysteroid dehydrogenase type 2
Steroidogenic acute regulatory protein
GnRH receptor
AMH
Inhibin ␣
P450 aromatase
17␤-Hydroxysteroid dehydrogenase type 1
P450 side chain cleavage
17␤-Hydroxysteroid dehydrogenase type 1
3␤-Hydroxysteroid dehydrogenase type 1
P450 side chain cleavage
17␣-Hydroxylase
Glycoprotein hormones, ␣⫺subunit
GnRH receptor
Adenosine deaminase
Leukemia inhibitory factor receptor
Placental lactogen I
Proliferin
NK2 homeobox 1
Gnrh1
Cga
Tshb
Gnrhr
Amh
Inhbb
Dmrt1
Fshr
Cldn11
Tes
Clmp
Sry
Sox9
Inha
Star
Cyp19a1
Cyp17a1
Cyp11a1
Lhcgr
HSD3B2
Star
GNRHR
Amh
Inha
Cyp19a1
(HORSE) HSD17B1
Cyp11a1
HSD17B1
HSD3B1
Cyp11a1
CYP17A1
CGA
GNRHR
Ada
LIFR
Prl3d1
Prl2c2
Nkx2–1
GATA4
GATA2/4
GATA2
Uncharacterized
GATA1/4/6
GATA1/4
GATA4
GATA1/4
GATA1/4/6
Uncharacterized
GATA1/6
GATA4
GATA4
GATA1/4
GATA1/4/6
GATA1/4/6
GATA4
GATA4
GATA4
GATA4/6
GATA4
Uncharacterized
GATA4
GATA4
GATA4
Uncharacterized
GATA4
GATA3
Uncharacterized
GATA4
GATA4/6
GATA2/3
GATA2/3
Uncharacterized
Uncharacterized
GATA2/3
GATA2
Uncharacterized
e
e, t
e, t, c,g
e, t
e, t,g
e, t
e, t
e, t, c
e, t, c,s
e, t
e, t, c
g
g
e, t, s
e, t, c
e, t
g
g
e, t
e, t, s
e, t, c
e, t
t
e, t
e, t, c, s
e
e, t
e, t
e, t
e, t
e, t
e, t
e, t
t
e, t
e, t, g
g
t
46
48
21, 52, 217
135
83, 88, 140, 141
218
219
220, 221
94
222
93
88
89, 90
36, 78, 105, 223
34, 105, 134, 224
105
88
88
196
35
132–134
135
76
131
120, 136, 137
138
139
150
151
139
38
48
149
147
148
143–145
145
65
PTH
P450 side chain cleavage
17␣-hydroxylase
Dehydroepiandrosterone-sulfotransferase
3␤-Hydroxysteroid dehydrogenase
Cytochrome b5
Paired box gene 4
Glucagon
Pth
CYP11A1
CYP17A1
SULT2A1
HSD3B2
CYB5
Pax4
Gcg
Uncharacterized
GATA6
GATA4/6
GATA6
GATA4/6
GATA6
Uncharacterized
GATA4/6
t
t
e, t, c
e, t
e, t
e, t
e, t
e, t
56
156
38, 156
156, 160
35
159
225
70
Testis
Ovary
Placenta
Thyroid and
Parathyroid
Adrenal
Pancreas
Refs.
e, EMSA and/or DNA footprinting; t, transfection data; c, ChIP; g, genetic (mouse) data; s, small interfering RNA-mediated
knockdown data.
58–63). Whereas mutations involving the first zinc finger result in either a loss of interaction with Friend of
GATA (FOG) transcriptional partners or altered DNAbinding affinity, those involving the GATA3 second
zinc finger or adjacent basic amino acids result in a
loss of DNA-binding (58). Although no GATA factor has
yet been reported to regulate thyroid development, at
least two thyroid-expressed genes, Nkx2–5 and
Nkx2–1, have been shown to be under GATA control in
the heart and lung, respectively (64, 65). Therefore, a
similar regulation in the thyroid would not be unlikely.
Pancreas
The mammalian pancreas is a mixed exocrine and
endocrine gland that is formed from the fusion of
dorsal and ventral buds of the foregut endoderm. In
recent years, our understanding of pancreatic development has benefited from the identification of essential transcription factors implicated in this process
such as pancreatic and duodenal homeobox 1 (PDX1)
and neurogenin 3 (NEUROG3) (66, 67). The cardiac
subfamily of GATA factors are well-known markers of
Viger et al. • Minireview
several endodermal derivatives including yolk sac,
lung, stomach, gut, and pancreas (5). GATA4 and
GATA6 have overlapping expression profiles in the
early pancreas (68, 69). GATA4 then becomes limited
to exocrine tissue and GATA6 to a subpopulation of
endocrine cells (68). GATA6, but not GATA4, has also
been shown to interact with Nkx2.2 (68), a critical islet
transcription factor. In the same study, transgenic
mice expressing a GATA4- or GATA6-Engrailed dominant repressor fusion protein in the pancreatic epithelium and in the islet revealed an important role for
GATA6, but not GATA4, in early pancreas specification
(68). Expression of the GATA6-Engrailed transgene
had two distinct phenotypes: agenesis of the pancreas
or a reduction in pancreatic tissue. In the latter, all
pancreatic cell types were significantly reduced, having few differentiated endocrine cells within enlarged
ductal structures (68). In contrast to these findings,
others have reported that GATA4 colocalizes with
early glucagon-positive cells as early as e12.5 in the
mouse and that GATA4 is able to transactivate the
glucagon (Gcg) gene promoter in vitro (70). The same
study also demonstrated that mutation of the GATA
binding element in the Gcg promoter reduces its basal
promoter activity in glucagon producing cells by 55%.
In another study, the development of the ventral but
not dorsal pancreas is completely absent in Gata4⫺/⫺
embryos, and Gata6⫺/⫺ embryos display a similar but
less dramatic phenotype (71). GATA4 has been found
to be frequently overexpressed and infrequently methylated in human pancreatic cancers, whereas GATA5
is likely hypermethylated during pancreatic cancer development (72).
Testis
Reproductive tissues are prominent sites of GATA expression. In the gonads, GATA-like proteins are evolutionarily conserved because they are found in a variety species ranging from worms to humans (73, 74).
In mammals, four GATA factors exhibit gonadal expression (GATA1/2/4/6), and with the exception of
GATA2 (75), this expression is exclusive to the somatic
cell population (73, 74) (Fig. 2). The testis contains two
major somatic cell types that facilitate spermatogenesis: Sertoli cells, which are the supporting cell lineage, and Leydig cells, the steroidogenic cell lineage.
GATA factors have been described in both cell types in
several species starting from the early stages of testis
differentiation to adult cells (74). Sertoli cells express
GATA4 from the onset of their differentiation through
to adulthood where its level of expression is considered to be constant regardless of the stage of germ
cell maturation (76–83). GATA6 is also present early
and is maintained in adult Sertoli cells (78, 80, 84).
Finally, a third GATA factor, GATA1, is expressed by
Sertoli cells, but the temporal expression of GATA1 in
this lineage differs from that of other GATA members.
GATA1 is first detected in the immature animal in
Sertoli cells of all the tubules, concomitantly with the
Mol Endocrinol, April 2008, 22(4):781–798 785
Fig. 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.
first wave of spermatogenesis (83, 85). In the adult
animal, GATA1 expression in Sertoli cells in stages
VI–IX of the seminiferous epithelium cycle coincides
with the androgen-sensitive VII–VIII stages and appears to be dependent on the presence of maturing
germ cells (79, 85). Although both GATA4 and GATA6
have been described in Leydig cells (78, 83, 84),
GATA4 is by far the predominant GATA factor of this
cell type, especially in rodents. GATA4 has also been
reported in Sertoli and Leydig cell tumors (86).
Because of the critical role of GATA factors in hematopoietic and cardiac development and the corresponding early embryonic lethality associated with Gata-null
mice, alternative strategies have had to be developed to
unravel their function in testis differentiation and physiology. Conditional knockout of GATA1 in Sertoli cells
failed to yield a significant phenotype, most likely due to
the redundancy of multiple GATA factors in this cell type
(87). Other approaches, however, have begun to give
clues into the roles of GATA4 in testis cell differentiation.
For example, mice homozygous for a GATA4 variant that
cannot interact with its cofactor FOG2 (Gata4ki/ki) or homozygous for a FOG2-null mutant (Fog2⫺/⫺) exhibit abnormal testis morphogenesis resulting from a failure of
Sertoli cells to differentiate (88). On a molecular level, this
appears to be due to a significant reduction in transcription of the testis-determining gene Sry (88), as well as a
block in Sox9 expression (89, 90). Whether Sry and Sox9
are direct targets of a GATA4/FOG2 complex, however,
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Mol Endocrinol, April 2008, 22(4):781–798
remains to be demonstrated. The Gata4ki/ki and Fog2⫺/⫺
mice also fail to express anti-Müllerian hormone (Amh) as
well as several steroidogenic markers [cytochrome P450
side chain cleavage (Cyp11a1), cytochrome P450 17␣hydroxylase/17,20 lyase (Cyp17a1), and 3␤-hydroxysteroid dehydrogenase type 1 (Hsd3b1)], suggesting that
steroidogenic cell differentiation and/or gene expression
is equally under GATA4/FOG2 control (88). Indeed, a
recent study using chimeric mice has shown that that
GATA4 is directly required for Leydig cell differentiation
in the fetal mouse testis (91). Additional indirect support
for a role for GATA factors in Leydig cells has come from
the characterization of GATA-like protein 1 [GLP1 (Glp1)]
knockout mice (92). Glp1 is expressed in Leydig cells
where it appears to act as a repressor of GATA action
(92). In males, loss of GLP1 function correlates with an
early impairment of germ cell differentiation, suggesting
that a complex regulation of GATA proteins in Leydig
cells by GLP1, FOG2, and perhaps other modulatory
factors, is crucial for their function. Although these
mouse studies have illustrated the involvement of GATA
factors for early testis cell differentiation, other strategies
are still needed for the direct assessment of their function
in the mature testis.
Important insights into GATA function in the testis
have also come from promoter studies of putative target
genes in cell lines or primary cultures of Sertoli and
Leydig cells. Most of these GATA gene targets are either
correlated with early differentiation (Dmrt1, Sry, and
Sox9), or hormone synthesis such as the inhibin subunits
(Inha and Inhb), Amh, and multiple proteins and enzymes
of the steroidogenic pathway in Leydig cells (see Table
2). Interestingly, recent studies have identified genes encoding junctional proteins such as claudin 11 and Coxsackie- and adenovirus receptor-like membrane protein
(CLMP) as novel GATA targets in the testis (93, 94).
Although a scaffolding protein of the blood-testis barrier,
Cldn11 expression has been shown to be under germ
cell and androgen regulation (95, 96), with the androgen
regulation apparently mediated by GATA and NFYA
proteins (94).
Despite the long list of target genes for GATA factors
in testicular cells, we have only begun to scratch the
surface as to how these factors are themselves regulated. At the transcriptional level, it is now evident that
Gata1 expression in mouse Sertoli cells is dependent on
a cell-specific promoter (97–99) and is negatively regulated by FSH and cAMP (100). In contrast to GATA1,
gonadotropins and/or cAMP agonists have been shown
to induce Gata4 and/or Gata6 expression in several gonadal cell lines, including MSC-1 Sertoli cells and
mLTC-1 Leydig cells (78, 101). The dissection of the
Gata4 promoter has begun to reveal some of its transcriptional control mechanisms (102, 103). In transgenic
mice, the first 5 kb of the 5⬘-flanking region of the Gata4
gene is sufficient to recapitulate endogenous Gata4 expression in Sertoli cells throughout development (102).
Subsequent in vitro studies identified two GC-box motifs
and especially one E-box element within this ⫺118-bp
region that are crucial for Gata4 transcriptional activity in
Viger et al. • Minireview
both testicular and cardiac cells (102, 103). In Sertoli
cells, members of the upstream transcription factor
(USF) family of factors, especially USF2, bind to and
activate the Gata4 promoter via this critical E-box motif
(102). Gata4 regulatory sequences driving expression in
steroidogenic (Leydig) cells of the testis and ovarian cells
have yet to be identified.
In both Sertoli and Leydig cells, GATA4 activity is
modulated via cooperative interactions with other transcriptional regulators and/or cofactors (73, 74, 104).
These include the nuclear receptors steroidogenic factor
1 (SF-1/NR5A1) and liver receptor homolog 1 (LRH-1/
NR5A2), which cooperate with GATA4 to enhance
transcription from the Inha, Amh, P450 aromatase
(Cyp19a1), and 3␤-hydroxysteroid dehydrogenase type
2 (HSD3B2) promoters (27, 35, 36, 105). In testicular
cells, GATA1 and GATA4 also interact with FOG1 and
FOG2 (25, 26, 106). Although the FOG proteins do not
bind directly to DNA, they function as either enhancers or
repressors of GATA transcriptional activity depending on
the cell and promoter context being studied (25, 26, 28,
106–109). On GATA-dependent gonadal promoters,
however, in vitro data suggest that FOG proteins play a
strictly repressive role (110). In the mouse testis, FOG1
and FOG2 are coexpressed with GATA1/4/6 in Sertoli
and Leydig cells (79, 110). FOG1 is first detected in
Sertoli cells at e15.5; expression is maintained throughout development but eventually becomes restricted to
stage VII–XII tubules in the adult (79). FOG2 is expressed
earlier than FOG1 and can be detected as early as the
undifferentiated gonad stage in both sexes (76). After sex
determination, testicular FOG2 expression is rapidly
down-regulated by e15.5, leaving only the testis capsule
and Leydig cells as significant sites of expression (79).
FOG2 then reappears after birth and, like FOG1, eventually becomes restricted to stage VII–XI tubules in the
adult testis (79). Different mouse models have clearly
identified a role for a GATA4/FOG2 complex in early
testis differentiation, acting upstream of Sry and Sox9
(88–90). However, it remains to be shown whether these
genes and other GATA targets in the testis are directly
modulated by either FOG-mediated coactivation or
corepression.
GATA4 is also a target for posttranslational modifications such as phosphorylation (34, 111–117). In gonadal
cells, activation of the cAMP/protein kinase A (PKA) signaling pathway is a major mechanism for conveying the
hormone responsiveness of many genes. In this classic
pathway, PKA phosphorylates cAMP response element
(CRE)-binding protein (CREB), which is then recruited
along with the CREB-binding protein (CBP) coactivator
to activate genes possessing CRE in their promoters. In
MA-10 Leydig cells, GATA4 is directly phosphorylated by
PKA on a specific serine residue (Ser261) (114). Phosphorylation of GATA4 allows for synergistic interactions
with different transcription factors including CCAAT/enhancer-binding protein (C/EBP␤) and NR5A2 (34, 35)
and permits recruitment of the CBP transcriptional coactivator much like CREB (114). This leads to robust
stimulation of transcription from gonadal promoters such
Viger et al. • Minireview
as Star, Inha, and HSD3B2 (34–36, 114). PKA is not the
sole kinase known to target the GATA4 protein. Indeed,
in the heart, phosphorylation of GATA4 at Ser105 via the
MAPK signaling pathway plays a crucial role in modulating its GATA4 activity in cardiomyocytes (111, 112,
118). Although GATA4 Ser105 has been shown to be
constitutively phosphorylated in porcine granulosa cells
(119), and appears to contribute to the FSH-induced
up-regulation of Cyp19a1 expression in these same cells
in the rat (120), its significance in testicular cells remains
to be demonstrated.
Ovary
The fetal ovary has been shown to express three GATA
factors: GATA2, -4, and -6 (Fig. 2). In the mouse,
GATA2 is specific for germ cells but only for a brief
period during fetal development (e11.5–e15.5) (75).
GATA4 is first detected in the mouse coelomic epithelium and porcine urogenital ridge of both XX and XY
embryos (76, 79, 81, 83). At this time, GATA4 and its
cofactor FOG2 label the somatic cell population of the
developing gonad (76, 79). Subsequently, GATA4 and
FOG2 continue to be expressed at high levels in ovarian somatic cells over the entire fetal period (76).
GATA4 expression patterns are similar in the fetal rat
and porcine ovary; the somatic, pregranulosa or follicular cells are GATA4 positive, whereas germ cells do
not express this factor (80, 81). In the fetal rat ovary,
GATA6 is present in both postmitotic germ cells and
the ovarian epithelium (80). In the human fetal ovary,
GATA4 is strongly expressed in pregranulosa/stromal
cells as early as gestational wk 13 and 14, when primordial follicles are not yet evident (121). By wk 16–33,
GATA4 localizes to granulosa cells (121). Like GATA4,
GATA6 and FOG2 are expressed in human fetal somatic cells but can also be detected in occasional
germ cells (unpublished data). Thus, much like the
testis, the abundant expression of GATA proteins, particularly GATA4, in the fetal ovary suggest that they
play key roles in the early steps of ovarian differentiation.
In the postnatal ovary, GATA4 and GATA6 are the
predominant GATA factors. GATA4 expression is negligible in primordial follicles of both the mouse and human
ovary (76, 80, 101, 122, 123). GATA4 expression initiates
in granulosa cells at the onset of follicle growth (i.e. their
initial recruitment) and their transformation into primary
follicles (76, 101, 122, 123). As follicular growth proceeds, granulosa cells of healthy preantral and antral
follicles express GATA4, where it localizes to cumulus
and mural granulosa cells, theca cells, and stromal cells
(76, 80, 101, 122–124). In luteal glands, GATA4 expression is low or negligible in mice and humans (76, 101,
123). However, in the rat and pig, GATA4 is expressed in
peripheral cells of new luteal glands; expression is downregulated as these structures regress (80, 124). Thus,
GATA4 expression is clearly linked to both structural and
functional changes in the postnatal ovary of different
mammalian species. GATA6 is also expressed in multiple cell types of the mouse, pig, and human postnatal
Mol Endocrinol, April 2008, 22(4):781–798 787
ovary. These include oocytes, luteal glands, and granulosa and theca cells of larger follicles (80, 101, 122–124).
Whereas GATA4 expression in granulosa cells is usually
down-regulated in follicles undergoing atresia, GATA6
expression in rodents is retained at this stage (80, 101).
In humans, GATA6 and FOG2 expression patterns are
similar; primary follicles have negligible or weak immunoreactivity, but in later follicular stages, GATA6 and
FOG2 proteins are detected in most granulosa cells,
occasional oocytes, and luteal glands (122, 123). In the
mouse, only a few granulosa cells of primordial follicles
readily express FOG2 protein. In antral follicles, FOG2
expression is often down-regulated, whereas GATA4 expression is retained (76).
Of the endocrine and paracrine regulators of folliculogenesis, gonadotropins as well as TGF␤ signaling have
been linked to the regulation of ovarian GATA function.
Gonadotropins have a fundamental impact on ovarian
folliculogenesis, especially FSH, which is required for the
development from preantral to antral follicles (125). In
FSH-unresponsive ovaries of women with an inactivating
mutation in the FSH receptor gene (FSHR), GATA4 is
absent in the large pool of primordial follicles as compared with healthy ovaries (126). However, granulosa
cells in the few primary follicles seen in these patients do
express GATA4 protein, suggesting that either FSH or
FSH receptor is not required for the initial activation of
GATA4 expression. In Fshr-null mice bearing follicular
arrest at the preantral stage, Gata4 expression is, however, impaired in preantral follicles compared with agematched wild-type animals (127). In vitro studies have
further established the link between gonadotropins and
the regulation of GATA4 and/or GATA6 action in the
ovary. Like testicular cells (114), the transcriptional activity of GATA proteins is likely induced by FSH/cAMP/
PKA-mediated phosphorylation in granulosa cells (124).
In murine granulosa tumor cells, which resemble normal
granulosa cells, FSH and forskolin up-regulate Gata4
mRNA levels (101). Moreover, treatment of immature
3-wk-old mice with pregnant mare serum gonadotropin
(PMSG) enhances follicular expression of Gata4 and
Gata6 transcripts (101). Similarly, in primary rat granulosa
cells, FSH up-regulates GATA4 mRNA and protein levels
(120), whereas in immature human granulosa cells, obtained from in vitro maturation of oocytes during fertility
treatments, FSH was shown to up-regulate GATA6
mRNA levels (128). In cultured preovulatory human granulosa cells, which luteinize during in vitro culture, treatments with recombinant human chorionic gonadotropin
or 8-Br-cAMP had no effect on GATA4 and FOG2
steady-state mRNA levels, whereas GATA6 mRNA levels were modestly but significantly up-regulated (123).
The effects on GATA6 rather than GATA4 likely reflect
the luteinized phenotype of human granulosa cells.
TGF␤ regulation of GATA target genes has been previously demonstrated in both cardiac and T helper cells
(129, 130). Recent results also support a role for GATA4
in TGF␤ signaling in the ovary. In mouse granulosa tumor
cells TGF␤ is able to up-regulate GATA4 protein levels
(131). Furthermore, TGF␤ activation of the Inha pro-
788 Mol Endocrinol, April 2008, 22(4):781–798
moter, a GATA target in both the testis and ovary (Table
2), is blocked when the critical GATA binding sites are
mutated (131). GATA4 interacts with Smad3 in granulosa
tumor cells, suggesting a role for GATA4 in the transcriptional complex activated by the TGF␤-signaling pathway
in the ovary. The proposed role for TGF␤ and other
signaling mechanisms in the regulation of GATA4 activity
in gonadal cells is presented in Fig. 3.
Much like the testis, important insights into the role of
GATA factors in ovarian function have come from an
analysis of potential target gene promoters in ovarian
cells. Because somatic cells of both the ovary and testis
express similar GATA proteins, it is not surprising that
GATA factors have similar target genes in these two
tissues (Table 2). To date, proposed GATA-dependent
genes in the ovary include Star (132–134), GNRHR (135),
Inha (131), Cyp19a1 (120, 136, 137), 17␤-hydroxysteroid
dehydrogenase type 1 (HSD17B1) (138), Cyp11a1 (139),
and Bcl2 (unpublished data). One of the first GATA target
genes to be described in gonadal cells was AMH (83). In
vitro and in vivo studies have provided strong evidence
that the mouse and human AMH promoter, at least in the
testis, is an important target for GATA4 (140, 141). Although exclusive to the fetal testis, the anti-Müllerian
Fig. 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/enhancerbinding protein (C/EBP␤), and CBP. In murine and rat granulosa cells, signaling elicited by gonadotropins or TGF␤ family members increases Gata4 transcription. TGF␤-mediated
activation of Smad3 and its cooperation with GATA4 also
leads to robust transcription of gonadal genes such as Inha
(see text for references).
Viger et al. • Minireview
hormone (AMH) is nonetheless produced by granulosa
cells of the postnatal ovary where GATA4 is also found
(142). Therefore, a similar role for GATA4 in AMH gene
regulation in the ovary is likely.
Placenta
GATA factors in placental cells were initially described
in studies of ␣GSU (CGA) transcription in the human
trophoblast-derived JEG-3 choriocarcinoma cell line
(48). Nuclear extracts of JEG-3 cells were shown to
contain GATA2 and GATA3 protein capable of binding
to a consensus GATA motif in the proximal CGA promoter (48). Moreover, mutation of the ␣GSU GATA
element dramatically reduced CGA promoter activity
in JEG-3 cells, suggesting that GATA2 and/or GATA3
is an important contributor to CGA transcription in the
placenta (48). Subsequent Northern blot and in situ
hybridization studies revealed that the Gata2 and
Gata3 transcripts are abundantly expressed in mouse
placenta, localizing predominantly to trophoblast giant
cells (143). In these cells, the murine or ovine genes
encoding for the placental hormones placental lactogen 1 (PRL3D1) and proliferin (PRL2C2) have been
proposed to be regulated by GATA2 and/or GATA3
(143–145). Indeed, although mice lacking either the
Gata2 or Gata3 gene develop trophoblast giant cells,
placental Prl3d1 expression is nonetheless reduced by
50% in these animals (145). For the Prl2c2 gene, a
similar 50% reduction in expression was observed in
Gata3-null placentas, and this reduction was even
more pronounced (5- to 6-fold) in Gata2-null placentas
(145). Proliferin is an angiogenic hormone known to
stimulate endothelial cell migration and neovascularization of the placenta (146). Consistent with a role for
GATA2 in Prl2c2 expression, decidual tissue adjacent
to Gata2-null placentas has been reported to exhibit
less neovascularization as compared with wild-type
tissue (145).
In vitro studies have also identified other placentaexpressed gene promoters as potential targets for regulation by GATA or GATA-like factors. These include the
mouse promoters for adenosine deaminase (Ada) (147)
and Cyp11a1 (139) and the human promoters for leukemia inhibitory factor receptor (LIFR) (148), GnRH receptor
(GNRHR) (149), (HSD17B1) (150), (HSD3B1) (151), and
(CYP17A1) (38). Whether these genes are actual targets
in vivo, however, awaits further genetic studies.
Adrenal
The adrenal cortex arises from mesodermal precursors that also give rise to gonadal steroidogenic cells
(152). The human fetal adrenal cortex consists of a
large inner zone, termed the fetal zone, and a thin
outer rim of more immature cells, known as the definitive zone (152). After birth, the fetal zone regresses. In
late gestation, the definitive zone begins to partition
into anatomically and functionally distinct compartments: the zona glomerulosa, zona fasiculata, and
Viger et al. • Minireview
zona reticularis (152). In the mouse adrenal, the zona
glomerulosa and zona fasciculata are well defined, but
there is no discernable zona reticularis. The adrenal
cortex of the young mouse contains an additional
layer, termed the x-zone, which is adjacent to the
medulla and is analogous to the fetal zone of the
human adrenal cortex (153).
GATA6 is abundantly expressed in the adrenal cortex
throughout development (38, 154, 155). During human
fetal development, GATA6 is evident in both the fetal and
definitive zones of the adrenal cortex (154). In the adult,
GATA6 is expressed in the zona reticularis and to a lesser
extent the zona fasciculata (154, 156, 157), but its pattern
of expression during early childhood and adrenarche has
not been established. Based on this distribution and
promoter analyses described below, GATA6 is postulated to play a key role in the production of adrenal
androgens and possibly also glucocorticoids (156). In the
mouse, GATA6 is expressed in both the fetal and adult
adrenal cortex (154), suggesting a role beyond merely
adrenal androgen biosynthesis. Although evidence for
the involvement of GATA6 in adrenal steroidogenesis is
accumulating, genetic proof that GATA6 is required for
adrenocortical function is lacking.
By comparison, GATA4 has a more restricted pattern
of expression during adrenocortical development and
therefore is presumed to have a limited role in the function of this tissue (154). During human development,
GATA4 mRNA is evident in the fetal zone of the adrenal,
but there is only weak expression of this transcript in the
adrenal cortex postnatally (154). Similarly, Gata4 is transiently expressed in the mouse adrenal cortex during
fetal but not postnatal development (154), a pattern reminiscent of Cyp17a1 in the mouse (158). Given their overlapping patterns of expression, it is possible that GATA4
enhances expression of Cyp17a1 in the fetal adrenal,
although there is no direct proof of this. Studies of mice
harboring Gata4 loss-of-function mutations suggest that
this transcription factor is not required for the differentiation of fetal adrenocortical cells (88, 154).
Consistent with its proposed role in the biosynthesis of
adrenal androgens and other corticoids, GATA6 has
been shown to act in synergy with SF-1 (NR5A1) and
other factors to enhance the transcription of CYP11A1
(156), CYP17A1 (38), cytochrome b5 (CYB5) (159), hydroxysteroid sulfotransferase (SULT2A1) (156, 160, 161),
and HSD3B2 (35) in cell lines (see Table 2). In the case of
the CYP17A1 promoter, GATA6 does not act through a
GATA response element but instead through interactions
with another transcription factor, specificity protein 1
(SP1) (38). In the case of CYB5, GATA6 enhances promoter activity through interactions with specificity protein 3 (SP3) (159). GATA4 can substitute for GATA6 in
transactivation studies of the CYP17A1 promoter (38),
suggesting that GATA4 may serve to augment CYP17A1
expression during fetal development. In addition to normal adrenal cortex, GATA4 may regulate gene expression in disease states (described below).
The differentiation, growth, and survival of steroidogenic cells in the adrenal gland are controlled by a di-
Mol Endocrinol, April 2008, 22(4):781–798 789
verse array of hormones. Endocrine hormones and paracrine factors traditionally associated with the function of
gonadal steroidogenic cells, such as LH, inhibins, and
activins, also influence the differentiation, proliferation
and function of adrenocortical cells, both in physiological
and pathophysiological states. There is no direct evidence that GATA6 is hormonally regulated in the normal
adrenal. Steady-state levels of Gata6 mRNA in the adrenal gland do not change markedly in mice treated with
ACTH or dexamethasone (157), nor does there appear to
be a diurnal variation in GATA6 expression in the adrenal.
Administration of dibutyryl cAMP to NCI-H295A human
adrenocortical cells has been shown to increase GATA6
mRNA levels, raising the possibility of hormonal regulation of GATA6 in the human adrenal cortex, but the
physiological relevance of this finding in vivo remains to
be established. GATA6 protein is down-regulated in response to mitogenic signals in some cell types (162,
163), but there is no evidence supporting a role for
GATA6 during proliferation in the adrenal cortex. Human
chorionic gonadotropin up-regulates Gata4 and LH receptor (Lhcgr) expression in a dose-dependent manner
(164). GATA4 has a role in the induced, but not basal,
regulation of the LH receptor (Lhcgr) promoter in adrenocortical tumor cells. Ectopic expression of GATA4 in
the adrenal heralds the appearance of neoplastic cells
(164), and this factor may serve to integrate intracellular
signals evoked by different hormones.
GATA FACTORS AND ENDOCRINE DISEASE
Gonadal Disorders and Tumorigenesis
To date, reports of gonadal disorders involving GATA4
or its associated cofactors have been scarce. Human
mutations in the NR5A1 gene have been identified in
individuals with 46,XY sex reversal with gonadal dysgenesis and adrenal insufficiency (165–167). Some of
the cases involved retained Müllerian duct derivatives,
indicating insufficient AMH production during fetal life.
One of the heterozygous NR5A1 mutations (G35E)
was found to act as a dominant-negative competitor of
the synergism between GATA4 and the wild-type
NR5A1 protein at the level of the AMH promoter (168).
This suggested that proper GATA4/SF-1 is essential
for normal AMH transcription in humans (168). Although not targeting the GATA4 gene itself, a recently
described de novo t(8;10) chromosomal translocation
associated with heart defects and hypergonadotropic
hypogonadism has been linked to the gene encoding
the GATA4 cofactor FOG2 (169). The resulting truncated FOG2 protein, however, did not appear to impair
AMH expression because the patient had no signs of
Müllerian duct retention. Thus, unlike the mouse (88),
FOG2 might be dispensable for the initiation of testicular development in humans.
In vitro studies have suggested roles for GATA factors
in the regulation of steroidogenesis in both gonadal and
adrenal cells (104, 156). Patients with polycystic ovary
790
Mol Endocrinol, April 2008, 22(4):781–798
syndrome (PCOS) have hyperandrogenism of both ovarian and adrenal origin. The gene expression pattern as
well as the response to hormonal stimulation of PCOS
theca cells differs significantly from their normal counterparts (170, 171). Interestingly, steady-state GATA6
mRNA levels are augmented in PCOS theca cells due to
increased gene transcription and stability of the GATA6
transcripts (172). No sequence variations at the GATA6
locus, however, were associated with PCOS patients
(172), suggesting that regulatory factors acting at the
level of the GATA6 promoter might be differentially expressed in normal vs. PCOS theca cells.
Ovarian carcinomas account for up to 90% of ovarian
cancer and typically have a poor prognosis related to a
delay in detection. They originate from the surface epithelium and occur in various forms, the most common
being serous carcinoma. The serous carcinomas commonly exhibit loss of heterozygosity (LOH) in the locus
8p21–23, which bears the GATA4 gene. In mucinous
carcinomas, this LOH is less common (173). Of interest,
GATA4 protein expression is lost in practically all serous
carcinomas (516 of 528 samples studied) but in only
some mucinous carcinomas (26 of 75 samples studied)
(173). Moreover, in the mucinous carcinomas, the loss of
GATA4 expression correlates inversely with the grade
and clinical stage of the tumors (173). In general, LOH
correlates with loss of GATA4 expression in the tumors,
suggesting that loss of the other allele is enough to
completely silence GATA4 expression. More recent findings indicate that the GATA4 gene is often silenced in
ovarian carcinomas by histone modifications. In various
ovarian cancer cell lines, GATA4 expression is usually
negative due to methylation of its gene promoter (174,
175). However, none of the analyzed serous carcinoma
samples (n ⫽7) exhibited a GATA4 methylated state
(175), indicating that LOH is the only reason for the
absence of GATA4 expression in the serous subtype. In
one study, GATA4 was found to be expressed in most of
the studied ovarian carcinomas of different subtypes (43
of 50 samples); in contrast to previous findings (173), 30
of these tumors were of serous type, and only six were
GATA4 negative (176). Instead, the authors found a frequent loss of GATA6 protein correlated with a loss of
several markers of normal epithelium such as disabled-2,
collagen IV, and laminin (176). Taken together, loss of
GATA4 and/or GATA6 expression, due to LOH or histone
modifications, is likely involved in the dedifferentiation of
the ovarian epithelium and ovarian carcinogenesis.
Granulosa cell tumors (GCTs) are rare, accounting for
3–5% of all ovarian cancers (176, 177). They are steroidogenically active, typically causing precocious puberty,
disturbances in menstrual cycle, and endometrial hyperplasia or cancer (176, 177). Although poorly understood,
the pathogenesis of GCTs involves defects in the regulation of granulosa cell proliferation (178). Recent findings suggest that GATA4 and GATA6 play a role in granulosa cell tumorigenesis (122). The majority of the
analyzed 80 GCTs expressed GATA4 and GATA6 as well
as NR5A1 and FOG2 protein at levels comparable with
those in normal granulosa cells (122). However, negative
Viger et al. • Minireview
or weak GATA6 protein expression is associated with a
large tumor size, suggesting that GATA6 has a role in
suppressing proliferation (122). This hypothesis is supported by findings in both glomerular and vascular
smooth muscle cells, in which GATA6 is able to induce
cell cycle arrest by activating and/or stabilizing p21cip1
(Cdkn1a) expression (163, 179).
Thus, GATA4 likely has an opposing role to GATA6 in
granulosa cell tumorigenesis. GATA4 expression associates with aggressive behavior in a subgroup of GCTs,
suggesting that it may facilitate proliferation and suppress apoptosis in granulosa cells (122). The vast majority of the analyzed GCTs expressed GATA4 at an intermediate or high level corresponding to its expression in
normal granulosa cells (122). GATA4 expression associates with clinical stage (122); GATA4 expression is high in
60% of tumors spread outside the ovary (stage Ic and
beyond). Furthermore, high GATA4 expression correlates with recurrence risk of the GCT patients, suggesting that GATA4 immunostaining may have value as a
prognostic tool in human GCTs. The reasons for high
GATA4 expression in aggressive GCTs, however, remain
unknown and therefore need further study.
GCTs and adrenal tumors (described below) of both
mice and humans exhibit similarities in their GATA expression patterns. Given the common embryonic origin
of adrenocortical cells and ovarian granulosa cells, the
GATA4/GATA6 ratio may serve as an essential element
in the balanced regulation of proliferation vs. apoptosis.
Potential target genes involved in these processes in the
ovary include cyclin D2 (Ccnd2) and the antiapoptotic
genes Bcl2 and Bcl2l1, which have been shown to be
under GATA control in other organs (180–182). Cyclin D2
is essential for granulosa cell proliferation and plays a
role in GCT development (183, 184). Our unpublished
results show that GATA4 expression is associated with
CCND2 and BCL2 expression in GCTs and that the
proximal promoters of both genes are activated by
GATA4 in granulosa tumor cells.
Adrenal Disorders and Tumorigenesis
Although not normally expressed in the postnatal adrenal cortex, ectopic GATA4 production has been
linked to disease states in this tissue (e.g. adrenocortical tumors; see below). Given their expression patterns and target genes, it is reasonable to postulate
that GATA factors may be relevant to adrenal insufficiency or other diseases characterized by aberrant
steroidogenic gene expression alone or together with
other factors. For example, a de novo heterozygous
mutation (G35E) in the NR5A1 gene has been shown
to be responsible for adrenal insufficiency and
pseudohermaphroditism (185). This mutant specifically fails to synergize with GATA factors on the
HSD3B2 promoter (35). GATA6 immunoreactivity is
significantly diminished in most human adrenocortical
adenomas and carcinomas (157, 186). This decrease
in GATA6 expression may be an important event for
the escape of tumor cells from normal control mech-
Viger et al. • Minireview
anisms, although there is no direct proof of this
premise. Consistent with its proposed role in adrenal
androgen biosynthesis in the zona reticularis, GATA6
expression is retained in a significant fraction of virilizing adrenocortical tumors, especially carcinomas
(187, 188). GATA4 mRNA is expressed in only a small
proportion of human adenomas and carcinomas (157,
187, 188). Larger amounts of GATA4 mRNA have been
found among those presenting aggressive clinical behavior, although its value as a prognostic marker remains to be established (189).
Gonadectomy causes cells in the mouse adrenal cortex to transform into sex steroid-producing cells that are
histologically and functionally similar to gonadal tissue
(190). This phenomenon is strain dependent; susceptible
strains include CE, DBA/2J, and NU/J. When these mice
are gonadectomized, small, basophilic cells, known as A
cells, accumulate in the subcapsular region of the adrenal cortex (191). Type A cells express GATA4 and AMH
type 2 receptor (AMHR2) but lack expression of steroidogenic markers (164, 192). Functionally, A cells resemble stromal cells of the postmenopausal ovary, which
can metabolize cholesterol into oxysterols but have limited capacity for the synthesis of sex steroids (193).
Later, foci of large, sex steroid-producing cells, termed B
cells, appear in the adrenal cortex (194). B cells express
Gata4, Nr5a1, Lhcgr, Inha, Amh, estrogen receptor ␣
(Esr1), Cyp17a1, and an ovary-specific alternative splice
variant of Cyp19a1 (164, 192). Type B cells resemble
follicular theca cells from women with PCOS, a condition
marked by chronically elevated LH levels (195). Traditional adrenocortical cell markers, such as the melanocortin 2 receptor (MC2R) or enzymes for the synthesis of
corticosterone or aldosterone [e.g. steroid 21-hydroxylase (Cyp21a1), P450 11␤-hydroxylase (Cyp11b1), and
aldosterone synthase (Cyp11b2)] are not expressed in A
or B cells (164). Given that many of the genes expressed
in A and B cells, such as Lhcgr, Inha, Amh, and Cyp17a1,
harbor GATA-binding sites in their promoters, increased
GATA4 levels may be postulated to lead to their enhanced expression in these cells.
When Inha promoter-SV40 T-antigen transgenic mice
are subject to prepubertal gonadectomy, they develop
sex steroid-producing adrenocortical carcinomas by 5–7
months of age (196, 197). These adrenocortical carcinomas generally arise in the X-zone, but subcapsular pates
of type A and B cells can accompany the X-zone lesions.
The molecular markers of adrenocortical neoplasia in
these mice, Lhcgr, Inha, Gata4, and Cyp17a1, are similar
to those described in gonadectomized DBA/2J mice.
GATA6 is also down-regulated during adrenocortical tumorigenesis in these transgenic mice. The phenomenon
of gonadectomy-induced adrenocortical neoplasia has
also been observed in other small animals, including rats,
guinea pigs, hamsters, and ferrets (198). In the ferret
adrenal, GATA4 immunoreactivity can be seen in both
small and large neoplastic cells and seems to correlate
with the degree of nuclear and cytoplasmic atypia (199).
GATA4 is particularly abundant in anaplastic myxoid adrenocortical carcinomas but is absent from the spindle
Mol Endocrinol, April 2008, 22(4):781–798 791
cell component of adrenocortical tumors (199). Thus,
taken together, it seems likely that GATA4 serves an
essential function in gonadectomy-induced adrenocortical tumorigenesis, given its established role in differentiation of gonadal stroma (88).
SUMMARY
Over the past decade, it has become plainly evident
that the critical nature of GATA regulatory proteins is
not simply a matter of the cardiac and hematopoietic
systems. Indeed, the abundant expression of GATA
proteins in multiple cell types of various endocrine
organs along with their ever-expanding list of target
genes is a strong indication that these factors are
essential regulators of cell-specific gene expression
required for the development, differentiation, and
function of endocrine cells. One must be wary, however, that most studies to date have relied heavily on
in vitro transactivation assays, DNA-binding analyses,
and to a lesser extent chromatin immunoprecipitation.
Although steadily increasing, the number of reports
relying on genetics and other in vivo models remain
limited as are cases of human endocrine-related disorders associated with GATA mutations and/or deregulated GATA function. Although several studies have
implicated GATA factors in endocrine tumors, the underlying mechanisms remain to be elucidated. The
future challenge is then to continue applying genetic
models to validate the bulk of in vitro data that is
currently available. For some endocrine organs, this
appears to be a somewhat daunting task. This is particularly true of the gonads and adrenal where the
overlapping expression of different GATA proteins in
various cell types (see Fig. 2) and the potential for
compensatory mechanisms render individual Gata
gene knockout approaches in mice difficult to interpret. A case in point is the Sertoli cell-specific knockout of the Gata1 gene in the adult testis, which produced no overt testicular phenotype (87). In these
particular cases, more sophisticated approaches will
undoubtedly be required.
Acknowledgments
Drs. Jorma Toppari (University of Turku, Finland) and Timo
Otonkoski (University of Helsinki, Finland) are thanked for
critical reading of the manuscript.
Received November 16, 2007. Accepted December 21,
2007.
Address all correspondence and requests for reprints to: Robert
S. Viger, Ph.D., Ontogeny-Reproduction, Room T1-49, CHUQ Research Centre, 2705 Laurier Boulevard, Quebec City, Quebec,
Canada G1V 4G2. E-mail: [email protected]; or Markku
Heikinheimo, M.D., Ph.D., Children’s Hospital, P.O. Box 22, 00014,
University of Helsinki, Helsinki, Finland. E-mail: markku.
[email protected].
This work was supported in part by a grant from the
Canadian Institutes of Health Research (CIHR) to R.S.V. and
792 Mol Endocrinol, April 2008, 22(4):781–798
by a grant from the Sigrid Juselius Foundation to M.H. and
M.A. R.S.V. is titleholder of the Canada Research Chair in
Reproduction and Sex Development. S.M.G. was a recipient
of a postdoctoral fellowship from the CIHR Institute of Gender and Health. D.B.W. is supported by National Institutes of
Health Grant DK075618.
Disclosure Statement: The authors have nothing to
disclose.
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