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Results for “GATA3 Transcription Factor”

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At least 19 recordsLinked to original sources
PubMed2007

Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor.

The hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome is an autosomal dominant disorder caused by mutations of the dual zinc finger transcription factor, GATA3. We investigated 21 HDR probands and 14 patients with isolated hypoparathyroidism for GATA3 abnormalities. Thirteen different heterozygous germline mutations were identified in patients with HDR. These consisted of three nonsense mutations, six frameshifting deletions, two frameshifting insertions, one missense (Leu348Arg) mutation and one acceptor splice site mutation. The splice site mutation was demonstrated to cause a pre-mRNA processing abnormality leading to the use of an alternative acceptor site 8 bp downstream of the normal site, resulting in a frameshift and prematurely terminated protein. Electrophoretic mobility shift assays (EMSAs) revealed three classes of GATA3 mutations: those that lead to a loss of DNA binding which represent over 90% of all mutations, and involved a loss of the carboxy-terminal zinc finger; those that resulted in a reduced DNA-binding affinity; and those (e.g. Leu348Arg) that did not alter DNA binding or the affinity but likely altered the conformational change that occurs during binding in the DNA major groove as predicted by a three-dimensional modeling. These results elucidate further the molecular mechanisms underlying the altered functions of mutants of this zinc finger transcription factor and their role in causing this developmental anomaly. No mutations were identified in patients with isolated hypoparathyroidism, thereby indicating that GATA3 abnormalities are more likely to result in two or more of the phenotypic features of the HDR syndrome and not in one, such as isolated hypoparathyroidism.

Abnormalities, Multiple↗
PubMed1999

The transcription factor GATA3 is a downstream effector of Hoxb1 specification in rhombomere 4.

In this paper, we show that the transcription factor GATA3 is dynamically expressed during hindbrain development. Function of GATA3 in ventral rhombomere (r) 4 is dependent on functional GATA2, which in turn is under the control of Hoxb1. In particular, the absence of Hoxb1 results in the loss of GATA2 expression in r4 and the absence of GATA2 results in the loss of GATA3 expression. The lack of GATA3 expression in r4 inhibits the projection of contralateral vestibuloacoustic efferent neurons and the migration of facial branchiomotor neurons similar to Hoxb1-deficient mice. Ubiquitous expression of Hoxb1 in the hindbrain induces ectopic expression of GATA2 and GATA3 in ventral r2 and r3. These findings demonstrate that GATA2 and GATA3 lie downstream of Hoxb1 and provide the first example of Hox pathway transcription factors within a defined population of vertebrate motor neurons.

Animals↗
PubMed2002

Expression of the transcription factors GATA3 and Pax2 during development of the mammalian inner ear.

The transcription factors GATA3 and Pax2 are expressed throughout development of the mouse inner ear. We have used antibodies to study their temporal and spatial expression patterns from embryonic days E8-E16.5. The two factors show reciprocal relationships in the regional patterning of the early otocyst and cellular patterning within the sensory epithelia. GATA3 is expressed in the whole otic placode at E8. In the otocyst at E9.5-10.5, the distribution is lateral and complementary to the medial expression pattern of Pax2. Only Pax2 is expressed in the endolymphatic duct, but both factors are expressed in the cochlea. At E11.5-13.5, GATA3 is expressed strongly in the cochlea, but in the dorsal, vestibular region it is downregulated. In all sensory epithelia, downregulation coincides with sensory innervation. Pax2 is expressed in all sensory and some nonsensory epithelia, but within sensory epithelia at E16.5 it is restricted to hair cells. GATA3 is expressed throughout key periods of cell proliferation, fate determination, and differentiation and is not specifically associated with any of these processes. Expression persists most strongly in the main components of the developing auditory system. These include the auditory sensory epithelium, the afferent and efferent nerves, and the mesenchymal and ectodermal cells in regions that form key parts of the middle and outer ear. GATA3 is thus expressed in functionally distinct groups of cells that integrate to form a complete sensory system. The results suggest that both factors may be involved in tissue compartmentalisation, morphogenesis, and cell signalling.

Aging↗
PubMed2001

Transcription factor GATA3 and the human HDR syndrome.

Recently, a member of the GATA-binding family of transcription factors was shown to be involved in the human hypoparathyroidism, sensorineural deafness and renal anomalies (HDR) syndrome. Deletion-mapping studies and subsequent mutation analysis revealed that haploinsufficiency for GATA3 is the underlying mechanism of the HDR syndrome. Here we discuss the clinical characteristics of the HDR syndrome and present an overview of the role of GATA3 and related GATA-binding transcription factors during vertebrate embryonic development and their involvement in human disease.

Animals↗
PubMed2005

Differentiation of an auditory neuronal cell line suitable for cell transplantation.

The auditory neuroblast cell line US/VOT-N33 (N33), which is conditionally immortal, was studied as an in vitro model for the differentiation of spiral ganglion neurons (SGNs) and as a candidate for cell transplantation in rodents. It expresses numerous molecular markers characteristic of auditory neuroblasts, including the transcription factors GATA3, NeuroD, Brn3a and Islet1, as well as the neuronal cytoskeletal protein beta3-tubulin. It displays active migratory behaviour in vitro and in vivo. In the presence of the fibroblast growth factors FGF1 or FGF2 it differentiates bipolar morphologies similar to those of native SGNs. In coculture with neonatal cochlear tissue it is repelled from epithelial surfaces but not from native SGNs, alongside which it extends parallel neuronal processes. When injected into the retina in vivo, EGFP-labelled N33 cells were traced for 1-2 weeks and migrated rapidly within the subretinal space. Cells that found their way into the retinal ganglion cell layer extended multiple processes but did not express beta3-tubulin. The ability of N33 to migrate, to differentiate, to localize with native SGNs in vitro and to survive in vivo suggests that they provide an effective model for SGN differentiation and for cell transplantation into the ear.

Animals↗
PubMed2006

Transcriptome and phenotypic analysis reveals Gata3-dependent signalling pathways in murine hair follicles.

The transcription factor Gata3 is crucially involved in epidermis and hair follicle differentiation. Yet, little is known about how Gata3 co-ordinates stem cell lineage determination in skin, what pathways are involved and how Gata3 differentially regulates distinct cell populations within the hair follicle. Here, we describe a conditional Gata3-/- mouse (K14-Gata3-/-) in which Gata3 is specifically deleted in epidermis and hair follicles. K14-Gata3-/- mice show aberrant postnatal growth and development, delayed hair growth and maintenance, abnormal hair follicle organization and irregular pigmentation. After the first hair cycle, the germinative layer surrounding the dermal papilla was not restored; instead, proliferation was pronounced in basal epidermal cells. Transcriptome analysis of laser-dissected K14-Gata3-/- hair follicles revealed mitosis, epithelial differentiation and the Notch, Wnt and BMP signaling pathways to be significantly overrepresented. Elucidation of these pathways at the RNA and protein levels and physiologic endpoints suggests that Gata3 integrates diverse signaling networks to regulate the balance between hair follicle and epidermal cell fates.

Animals↗
PubMed2000

Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo.

By DNase I hypersensitivity analysis, we have identified an inducible, cyclosporin A-sensitive enhancer located 3' of the interleukin-4 (IL-4) gene. The enhancer binds the Th2-specific transcription factor GATA3 in vivo but is not perceptibly influenced by the absence of a second Th2-specific factor, cMaf. The antigen-inducible transcription factor NFAT1 binds the IL-4 enhancer and the IL-4 promoter only in stimulated Th2 cells; conversely, NFAT1 binds to the interferon (IFN)-gamma promoter only in stimulated Th1 cells. Our results support a model whereby transcription factors such as NFAT1, which are nonselectively induced in antigen-stimulated T cells, gain access to cytokine regulatory regions only in the appropriate subset of differentiated T cells in vivo. This restricted access enables antigen-dependent and subset-specific transcription of cytokine genes.

3' Untranslated Regions↗
PubMed2004

Long-range intrachromosomal interactions in the T helper type 2 cytokine locus.

The T helper type 2 (T(H)2) locus control region is important in the regulation of the genes encoding the cytokines interleukins 4, 5 and 13. Using the chromosome conformation capture technique, we found that in T cells, natural killer cells, B cells and fibroblasts, the promoters for the genes encoding T(H)2 cytokines are located in close spatial proximity, forming an initial chromatin core configuration. In CD4(+) T cells and natural killer cells, but not B cells and fibroblasts, the T(H)2 locus control region participates in this configuration. The transcription factors GATA3 and STAT6 are essential for the establishment and/or maintenance of these interactions. Intrachromosomal interactions in the T(H)2 cytokine locus may form the basis for the coordinated transcriptional regulation of cytokine-encoding genes by the T(H)2 locus control region.

Animals↗
PubMed2004

STAT6-dependent differentiation and production of IL-5 and IL-13 in murine NK2 cells.

NK cells differentiate into either NK1 or NK2 cells that produce IFN-gamma or IL-5 and IL-13, respectively. Little is known, however, about the molecular mechanisms that control NK1 and NK2 cell differentiation. To address these questions, we established an in vitro mouse NK1/NK2 cell differentiation culture system. For NK1/NK2 cell differentiation, initial stimulation with PMA and ionomycin was required. The in vitro differentiated NK2 cells produced IL-5 and IL-13, but the levels were 20 times lower than those of Th2 or T cytotoxic (Tc)2 cells. No detectable IL-4 was produced. Freshly prepared NK cells express IL-2Rbeta, IL-2RgammaC, and IL-4Ralpha. After stimulation with PMA and ionomycin, NK cells expressed IL-2Ralpha. NK1 cells displayed higher cytotoxic activity against Yac-1 target cells. The levels of GATA3 protein in developing NK2 cells were approximately one-sixth of those in Th2 cells. Both NK1 and NK2 cells expressed large amounts of repressor of GATA, the levels of which were equivalent to CD8 Tc1 and Tc2 cells and significantly higher than those in Th2 cells. The levels of histone hyperacetylation of the IL-4 and IL-13 gene loci in NK2 cells were very low and equivalent to those in naive CD4 T cells. The production of IL-5 and IL-13 in NK2 cells was found to be STAT6 dependent. Thus, similar to Th2 cells, NK2 cell development is dependent on STAT6, and the low level expression of GATA3 and the high level expression of repressor of GATA may influence the unique type 2 cytokine production profiles of NK2 cells.

Acetylation↗
PubMed2006

Nicotinic receptors mediate tumorigenic action of tobacco-derived nitrosamines on immortalized oral epithelial cells.

Frequent users of smokeless tobacco (ST) have an increased risk for developing oral cancer. Nicotine and its derivatives may contribute to tumorigenesis through stimulation of nicotinic acetylcholine receptors (nAChRs) in target cells. Emerging evidence indicates that nAChRs can be stimulated by the nicotine-derived nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) that can induce oral cavity tumors in laboratory animals. This study was designed to elucidate the receptor-mediated mechanisms of the initiation and progression of NNK-, and NNN-induced oral cancers. We used Het-1A cells that were found to express alpha3, alpha5, alpha7, alpha9, beta2 and beta4 nAChR subunits. Both NNK and NNN competed with nicotinic radioligands for binding to Het-1A cells. NNK showed a higher than NNN affinity to the [3H]nicotine-labeled binding sites, and NNN-to the [3H]epibatidine-sensitive nAChRs. NNK and NNN increased proliferative potential of Het-1A cells and produced an anti-apoptotic effect, which was alleviated by antagonists. alpha-Bungarotoxin was most effective against NNK and mecamylamine against NNN. Treatment of Het-1A cells with either NNK or NNN led to acquisition of capability of anchorage independent growth and ability to produce tumors in nude mice, both of which can be by inhibited by antagonists. To elucidate the signaling mechanisms, we studied transcription of the genes encoding the cell cycle, apoptosis and signal transduction regulators at both the mRNA and protein levels. The Het-1A cells stimulated with nitrosamines showed multifold increases of the mRNA transcripts encoding PCNA and Bcl-2, and upregulated expression of the transcription factors GATA3, nuclear factor-kappaB, and STAT-1. The STAT-1 protein-binding activity induced by NNK and NNN correlated with elevated gene expression. The obtained results establish the role of specific nAChR subtypes in tobacco-related carcinogenesis and open a novel avenue for oral cancer chemoprevention.

Humans↗
PubMed2005

5-aminoimidazole-4-carboxamide ribonucleoside: a novel immunomodulator with therapeutic efficacy in experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, is a Th1-mediated inflammatory demyelinating disease of the CNS. AMP-activated protein kinase was reported recently to have anti-inflammatory activities by negatively regulating NF-kappaB signaling. In this study, we investigated the prophylactic and therapeutic efficacy of an AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), in active and passive EAE induced by active immunization with PLP(139-151) or MOG(35-55) and in adoptive transfer of PLP(139-151)-sensitized T cells, respectively. In vivo treatment with AICAR exerted both prophylactic and therapeutic effects on EAE, attenuating the severity of clinical disease. The anti-inflammatory effects of AICAR were associated with the inhibition of the Ag-specific recall responses and inhibition of the Th1-type cytokines IFN-gamma and TNF-alpha, whereas it induced the production of Th2 cytokines IL-4 and IL-10. Treatment of PLP(139-151)-specific T cells in vitro with AICAR decreased their expression of T-bet in response to IL-12, a Th1 transcription factor, whereas in response to IL-4, it induced the expression and phosphorylation of Th2 transcription factors GATA3 and STAT6, respectively. Moreover, treatment of APCs in vitro with AICAR inhibited their capability to present the proteolipid protein peptide to PLP(139-151)-specific T cells. In an irrelevant Th1-mediated, OT-2 TCR transgenic mouse model, AICAR impaired in vivo Ag-specific expansion of CD4(+) T cells. Together, these findings show for the first time that AICAR is a novel immunomodulator with promising beneficial effects for the treatment of multiple sclerosis and other Th1-mediated inflammatory diseases.

AMP-Activated Protein Kinases↗
PubMed2006

Characteristics of hearing loss in HDR (hypoparathyroidism, sensorineural deafness, renal dysplasia) syndrome.

Haploinsufficiency of the zinc finger transcription factor GATA3 causes the triad of hypoparathyroidism, deafness and renal dysplasia, known by its acronym HDR syndrome. The purpose of the current study was to describe in detail the auditory phenotype in human HDR patients and compare these to audiometrical and histological data previously described in a mouse model of this disease. Pure tone audiometry, speech audiometry, speech in noise, auditory brainstem responses and transiently evoked otoacoustic emissions were measured in 2 patients affected by HDR syndrome. Both patients were affected by a moderate-to-severe sensorineural hearing loss. Speech reception thresholds were shifted and speech recognition in noise was disturbed. No otoacoustic emissions could be generated in either patient. Auditory brainstem response interpeak intervals were normal. The human and murine audiological phenotypes seem to correspond well. Hearing loss in HDR syndrome is moderate to severe, seems to be slightly worse at the higher end of the frequency spectrum and may be progressive with age. The absence of otoacoustic emissions and the loss of frequency selectivity suggest an important role for outer hair cells in causing the hearing loss.

Adult↗
PubMed1997

Regulation of aquaporin-2 gene transcription by GATA-3. off.

To evaluate the functional role of GATA motifs in the 5'-flanking region of a kidney-specific AQP-2 water channel gene, we sought to isolate a GATA factor(s) expressed in collecting ducts and determined the role on the AQP-2 promoter. Two cDNAs encoding GATA factors were isolated from rat kidney, whose sequences were highly homologous with human GATA-2 and -3. Reverse-transcription PCR using dissected nephron segments revealed that rat GATA-3 but not GATA-2 was expressed in collecting ducts, thus indicating that GATA-3 could interact with GATA motifs in the AQP-2 promoter. Transactivation experiments utilizing the rat GATA-3 expression vector indicated that rat GATA-3 increased the AQP-2 promoter activity about fourfold. These results indicated that GATA motifs in the 5'-flanking region of the hAQP-2 gene were functional cis-elements and that GATA-3 in collecting ducts may be one of the important regulators of AQP-2 expression in vivo.

Animals↗
PubMed2000

Genomic organization, chromosomal localization, and the complete 22 kb DNA sequence of the human GCMa/GCM1, a placenta-specific transcription factor gene.

The genomic sequence of the human GCMa/GCM1 gene, a mammalian homologue of Drosophila melanogaster GCM, was determined. Drosophila GCM is a neural transcription factor that regulates glial cell fate. The mammalian homolog however, is a placenta-specific transcription factor that is necessary for placental development. The 22 kb DNA sequence spanning the GCMa gene contains six exons and five introns, encoding a 2.8 kb cDNA. Overall genomic organization is similar for the human and mouse. Several potential binding sites for transcription factors like GATA, Oct-1, and bHLH proteins were found in the 5'-flanking region of the human gene. A DNA motif for GCM protein binding exists in the 5'-flanking region that is highly homologous with that of the mouse gene. The location of this gene was mapped to chromosome 6 using fluorescence in situ hybridization.

Animals↗
PubMed1998

Knock-in mutation of transcription factor GATA-3 into the GATA-1 locus: partial rescue of GATA-1 loss of function in erythroid cells.

Transcription factors of the GATA-family are essential for proper development of diverse tissues or cell types. GATA-1 is required for differentiation of two hematopoietic lineages (red blood cells and megakaryocytes), whereas GATA-3 is essential for T-cell development. Functional studies suggest that many properties of the GATA-family of proteins are shared and largely interchangeable. To test whether the function of GATA-1 in erythroid differentiation can be replaced by another GATA-factor, we generated a knock-in mutation of the GATA-1 locus in which GATA-3 cDNA was introduced by gene targeting. Mutant embryos (designated G1G3ki), though embryonic lethal, exhibit partial rescue, characterized by increased survival of erythroid precursor cells and improved hemoglobin production. The basis for the incomplete extent of rescue is likely to be complex, but may be accounted for, in part, by insufficient accumulation of GATA-3 protein (compared with the normal level of GATA-1). Our findings suggest that GATA-3 protein is functional when expressed in an erythroid environment and is competent to act on at least a subset of erythroid-expressed target genes in vivo.

Anemia↗
PubMed1999

Expression and genetic interaction of transcription factors GATA-2 and GATA-3 during development of the mouse central nervous system.

Here we examine the expression of transcription factors GATA-2 and GATA-3 during early stages of embryonic development in the central nervous system (CNS) of the mouse. GATA-2 is expressed as early as 9 dpc in the hindbrain, in ventral rhombomere 4, and transiently in ventral rhombomere 2 (r2). From 9.5 to 11.5 dpc, activation of the gene spreads to many sites of early neuronal differentiation, such as the olfactory bulbs, the pretectum, and the oculomotor nucleus in the midbrain, a thin stripe of cells lining the floor plate from the mesencephalon to the cervical spinal cord and a ventral column of cells spanning the neural tube from rostral hindbrain and including motor neuron as well as ventral interneuron precursors. GATA-3 is expressed in a pattern very similar to that of GATA-2. Distinguishing features are the lack of expression in r2 at 9 dpc and a slight delay in its activation. In addition, GATA-2 is activated in both the ventricular and the subventricular zones of the neural tube, whereas GATA-3 is restricted mainly to the subventricular zone. Expression analyses performed on GATA-2 -/- mouse embryos between E9.5 and 10.5 dpc established that: (i) the expression of GATA-3 in the developing CNS of the mouse embryo is dependent on the presence of GATA-2 and (ii) loss of GATA-2 leads to severe defects in neurogenesis, which strongly suggests that GATA-2 is involved, as in hematopoiesis, in the maintenance of the pool of ventral neuronal progenitors.

Animals↗
PubMed2001

Hemangioblast commitment in the avian allantois: cellular and molecular aspects.

We recently identified the allantois as a site producing hemopoietic and endothelial cells capable of colonizing the bone marrow of an engrafted host. Here, we report a detailed investigation of some early cytological and molecular processes occurring in the allantoic bud, which are probably involved in the production of angioblasts and hemopoietic cells. We show that the allantois undergoes a program characterized by the prominent expression of several "hemangioblastic" genes in the mesoderm accompanied by other gene patterns in the associated endoderm. VEGF-R2, at least from stage HH17 onward, is expressed and is shortly followed by transcription factors GATA-2, SCL/tal-1, and GATA-1. Blood island-like structures differentiate that contain both CD45(+) cells and cells accumulating hemoglobin; these structures look exactly like blood islands in the yolk sac. This hemopoietic process takes place before the establishment of a vascular network connecting the allantois to the embryo. As far as the endoderm is concerned, GATA-3 mRNA is found in the region where allantois will differentiate before the posterior instestinal portal becomes anatomically distinct. Shortly before the bud grows out, GATA-2 was expressed in the endoderm and, at the same time, the hemangioblastic program became initiated in the mesoderm. GATA-3 is detected at least until E8 and GATA-2 until E3 the latest stage examined for this factor. Using in vitro cultures, we show that allantoic buds, dissected out before the establishment of circulation between the bud and the rest of the embryo, produced erythrocytes of the definitive lineage. Moreover, using heterospecific grafts between chick and quail embryos, we demonstrate that the allantoic vascular network develops from intrinsic progenitors. Taken together, these results extend our earlier findings about the commitment of mesoderm to the endothelial and hemopoietic lineages in the allantois. The detection of a prominent GATA-3 expression restricted to the endoderm of the preallantoic region and allantoic bud, followed by that of GATA-2, is an interesting and novel information, in the context of organ formation and endoderm specification in the emergence of hemopoietic cells.

Allantois↗