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PubMed1997

The POU-domain factor Brn-3.0 recognizes characteristic sites in the herpes simplex virus genome.

The restriction of herpes virus latency to mammalian sensory ganglia has led to a search for tissue-specific regulatory molecules in these neurons which alter viral gene expression. We have recently shown that the POU-domain transcriptional regulator Brn-3.0 is abundantly expressed in the adult trigeminal ganglion. To begin to examine the hypothesis that Brn-3.0 might participate in the regulation of the HSV life-cycle, we used Brn-3.0 POU-domain protein as an affinity matrix, and biochemically screened the entire HSV genome for sites of Brn-3.0 binding. This screen identified several sites of the form TA/TA A T N A N TA/T, which significantly do not include the previously identified HSV octamer sequences. All of the selected sites occur in the <25% of the HSV genome which has not been assigned to open reading frames, suggesting that these sites may be transcriptional regulatory elements recognized by Brn-3.0 or another homeobox factor with similar DNA binding properties. However, these sites do not interact with Brn-3.0 with sufficiently high affinity to directly mediate transcriptional activation by Brn-3.0 alone in transfection assays. The experiments described also provide an effective general method for exhaustive screening of large viral genomes or sub-genomic fragments of eukaryotic DNA for sites of interaction with specific transcription factors.

Animals↗
PubMed1999

POU domain factor Brn-3b is essential for retinal ganglion cell differentiation and survival but not for initial cell fate specification.

While the mammalian retina is well understood at the anatomical and physiological levels, little is known about the mechanisms that give rise to the retina's highly ordered pattern or its diverse neuronal cell types. Previous investigations have shown that gene disruption of the POU-IV class transcription factor Brn-3b (Brn-3.2) resulted in the loss of most retinal ganglion cells in retinas of postnatal mice. Here, we used lacZ and human placental alkaline phosphatase genes knocked into the brn-3b locus to follow the fate of brn-3b-mutant cells in the developing retina. We found that Brn-3b was not required for the initial commitment of retinal ganglion cell fate or for the migration of ganglion cells to the ganglion cell layer. However, Brn-3b was essential for the normal differentiation of retinal ganglion cells; without it, the cells underwent enhanced apoptosis. Retinal ganglion cells lacking brn-3b extended processes at the appropriate time in development, but these processes were disorganized, resulting in a thinner optic nerve. Explanted retinas from brn-3b-null embryos also extended processes when cultured in vitro, but the processes were shorter and less bundled than in wild-type retinas. Ultrastructural and marker analyses showed that the processes of mutant ganglion cells had dendritic rather than axonal features, suggesting that mutant cells formed dendrites in place of axons. These results suggest that Brn-3b regulates the activity of genes whose products play essential roles in the formation of retinal ganglion cell axons.

Alkaline Phosphatase↗
PubMed1996

T antigen of human papovavirus JC stimulates transcription of the POU domain factor Tst-1/Oct6/SCIP.

Human papovavirus JC exhibits a strong tropism for glial cells in vivo. To a large extent, this effect is due to the pronounced glia specificity of viral gene expression, which is mediated by the specific interaction of glial transcription factors such as Tst-1/Oct6/SCIP with viral promoter sequences. Here we show that, in return, expression of the glial transcription factor Tst-1/Oct6/SCIP can be strongly activated by T antigen, the early gene product of JC virus, in a dose-dependent manner. In transient transfection experiments, stimulation by T antigen was entirely dependent on a 335-bp segment of the Tst-1/Oct6/SCIP gene promoter that included the transcriptional start site. The same fragment was also bound by purified T antigen in immunoprecipitation assays due to the presence of three closely spaced and tandemly oriented GAGGC pentamers. However, when this array of pentamers was mutated so that binding of T antigen was strongly reduced, T-antigen-dependent transcriptional activation remained unaffected. Thus, similar to viral late gene expression, transcriptional stimulation of the Tst-1/Oct6/SCIP gene by T antigen was not dependent on binding to GAGGC pentamers present within the promoter. Nevertheless, our data provide strong support for a model in which JC virus influences gene expression of its host cell via its early gene product in a manner favourable for its own propagation.

Animals↗
PubMed2002

Cross-repression, a functional consequence of the physical interaction of non-liganded nuclear receptors and POU domain transcription factors.

Nuclear receptors (NRs) and POU domain factors form two important transcription factor families for which several levels of functional interference have been described. In this study, the adopted orphan receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) were found to perform direct protein-protein interactions with Pit-1, a representative POU domain factor. The ligand-dependent interaction profile of Pit-1 with CAR, PXR, and the vitamin D receptor in solution was shown to be that of a corepressor. In the absence of receptor agonist Pit-1 inhibited the complex formation of NRs with the retinoid X receptor on DNA. Also in living cells, Pit-1 and Oct-1, another POU domain factor, behaved like corepressors of NR signaling, and Pit-1-mediated repression was found to involve histone deacetylases. Conversely vitamin D receptor, CAR, and PXR were shown to act as repressors of Pit-1 signaling in different cell lines (MCF-7, HaCaT, and GH4C1). This repression was found to be independent of histone deacetylases and seems to be based on a competition of NRs with coactivator and corepressor proteins for overlaying interaction interfaces on the surface of Pit-1. Taken together this study suggests that cross-repression should occur in all tissues in which POU domain factors and non-liganded NRs meet each other.

Amino Acid Sequence↗
PubMed2000

Abnormal polarization and axon outgrowth in retinal ganglion cells lacking the POU-domain transcription factor Brn-3b.

The POU domain transcription factor Brn-3b (also called Brn-3.2) is essential for the normal development of retinal ganglion cells (RGCs) in the mouse. Without Brn-3b, RGCs commit to their fate and migrate to the ganglion cell layer, but most cells die during fetal development. An earlier report (L. Gan et al., 1999, Dev. Biol. 210, 469-480) suggested that cell death was caused by abnormal axon formation. Here, we use retinal explants from wild-type and mutant embryos to show that brn-3b-deficient RGCs are not properly polarized and tend to form dendrites rather than axons. Compared with wild-type explants, neurites of RGCs from brn-3b-deficient retinal explants grew slower, were shorter, and did not fasciculate properly. Mutant neurites had more microtubules than wild-type controls, and the arrangement of microtubules and neurofilaments was characteristic of dendrites rather than axons. Neurites from individual mutant RGCs displayed abnormal polarity and had dendrite-like branches extending outward from their main axis. Most mutant RGCs exhibited abnormal migratory behavior, and their neurites labeled intensely with the dendrite marker MAP-2. A small number of mutant RGCs were not migratory, and their neurites were longer and labeled positively for the axon marker tau-1, suggesting that some RGCs were not as severely affected by the absence of Brn-3b as others. Although tau-1 was not observed in most mutant neurites, it did accumulate in mutant cell bodies, implying that the absence of Brn-3b caused a defect in axon transport. Thus, Brn-3b appears to control the activity of genes that function in establishing RGC polarity, and without Brn-3b, RGCs cannot extend normal axons.

Animals↗
PubMed2005

Functional equivalence of Brn3 POU-domain transcription factors in mouse retinal neurogenesis.

POU-domain transcription factors play essential roles in cell proliferation and differentiation. Previous studies have shown that targeted deletion of each of the three POU-domain Brn3 factors in mice leads to the developmental failure and apoptosis of a unique set of sensory neurons in retina, dorsal root ganglia, trigeminal ganglia and inner ear. The specific defects associated with the removal of each Brn3 gene closely reflect their characteristic spatiotemporal expression patterns. Nevertheless, it remains elusive whether Brn3 factors are functionally equivalent and act through a common molecular mechanism to regulate the development and survival of these sensory neurons. By knocking-in Brn3a (Brn3aki) into the Brn3b locus, we showed here that Brn3aki was expressed in a spatiotemporal manner identical to that of endogenous Brn3b. In addition, Brn3aki functionally restored the normal development and survival of retinal ganglion cells (RGCs) in the absence of Brn3b and fully reinstated the early developmental expression profiles of Brn3b downstream target genes in retina. These results indicate that Brn3 factors are functionally equal and that their unique roles in neurogenesis are determined by the distinctive Brn3 spatiotemporal expression patterns.

Animals↗
PubMed1992

POU domain transcription factors from different subclasses stimulate adenovirus DNA replication.

POU domain proteins constitute a family of eukaryotic transcription factors that exert critical functions during development. They contain a conserved 160 amino acids DNA binding domain, the POU domain. Genetic data have demonstrated that some POU domain proteins are essential for the proliferation of specific cell types, suggesting a possible role in DNA replication. In addition, the ubiquitous POU transcription factor Oct-1 or its isolated POU domain enhances adenovirus DNA replication. Here we compared the DNA binding specificities of POU domain proteins from different subclasses. They exhibit overlapping, yet distinct binding site preferences. Furthermore, purified Pit-1, Oct-1, Oct-2, Oct-6, Oct-4 and zebrafish POU[C] could all stimulate adenovirus DNA replication in a reconstituted in vitro system. Thus, activation appears to depend on a property common to most POU domain proteins. Adenovirus DNA replication is also stimulated by the transcription factor NFI/CTF. In contrast to NFI, the POU domain did not enhance binding of precursor terminal protein-DNA polymerase to the origin nor did it stabilize the preinitiation complex. These results suggest that the POU domain acts on a rate limiting step after formation of the preinitiation complex.

Adenoviridae↗
PubMed2003

Direct autoregulation and gene dosage compensation by POU-domain transcription factor Brn3a.

Brn3a is a POU-domain transcription factor expressed in peripheral sensory neurons and in specific interneurons of the caudal CNS. Sensory expression of Brn3a is regulated by a specific upstream enhancer, the activity of which is greatly increased in Brn3a knockout mice, implying that Brn3a negatively regulates its own expression. Brn3a binds to highly conserved sites within this enhancer, and alteration of these sites abolishes Brn3a regulation of reporter transgenes. Furthermore, endogenous Brn3a expression levels in the sensory ganglia of Brn3a(+/+) and Brn3a(+/-) mice are similar, demonstrating that autoregulation can compensate for the loss of one allele by increasing transcription of the remaining gene copy. Conversely, transgenic overexpression of Brn3a in the trigeminal ganglion suppresses the expression of the endogenous gene. These findings demonstrate that the Brn3a locus functions as a self-regulating unit to maintain a constant expression level of this key regulator of neural development.

Animals↗
PubMed1992

Brain 4: a novel mammalian POU domain transcription factor exhibiting restricted brain-specific expression.

The POU domain gene family of transcription factors share a conserved bipartite DNA binding domain, and exhibit distinct temporal and spatial patterns of expression during development, particularly in the forebrain. A cDNA encoding a new member of the POU-III class of the POU domain gene family, referred to as Brn-4, was isolated from a rat hypothalamic cDNA library. Like other mammalian POU-III genes previously characterized (Brn-1, Brn-2, Tst-1), Brn-4 transcripts are initially widely expressed at all levels of the developing neural tube, but in contrast to other previously described POU-III genes, are subsequently restricted to only a few regions of the adult forebrain, including the supraoptic and paraventricular nuclei of the hypothalamus. Brn-4 was shown to bind to DNA sequences containing the octamer motif and to trans-activate promoters containing this DNA binding motif, based on the actions of a unique N-terminal information. This ontogenic pattern of Brn-4 expression in concert with that of Oct-2 and Pit-1, indicates that certain POU domain genes potentially exert their primary functions widely during early neural development, and in a very limited set of neurons in the mature brain.

Amino Acid Sequence↗
PubMed2002

Expression of the POU-domain transcription factors SCIP/Oct-6 and Brn-2 is associated with Schwann cell but not oligodendrocyte remyelination of the CNS.

The class III POU-domain transcription factor SCIP/Oct-6 is expressed by promyelinating Schwann cells and, in tissue culture, by oligodendrocyte progenitors (OPs), but is down-regulated in both cells types as they differentiate. Although the expression of SCIP/Oct-6 has been examined in peripheral nerve remyelination, its expression in CNS remyelination has not been addressed. Using a toxin model of demyelination, in which the demyelinated axons are remyelinated in an age-dependent manner by both oligodendrocytes and Schwann cells, we have compared the expression of SCIP/Oct-6 mRNA with that of an OP marker (PDGF-alphaR), a marker of myelinating oligodendrocytes (PLP), and markers of myelinating Schwann cells (P(0) and Krox-20) by in situ hybridization. We have found that the expression of SCIP/Oct-6 mRNA precedes that of P(0) and Krox-20 mRNA expression, but bears little correlation with the expression profiles of either PDGF-alphaR or PLP mRNA. Moreover, there is a spatial correlation between the expression SCIP/Oct-6 mRNA and that of P(0) but not of PDGF-alphaR. These results indicate that SCIP/Oct-6 expression following CNS demyelination is associated with Schwann cell and not oligodendrocyte remyelination. We have also shown that another POU-domain transcription factor, Brn-2, is expressed during CNS remyelination, but that like SCIP/Oct-6, it too has an expression profile indicating that it is associated with the Schwann cell component of remyelination. In addition, we show that Brn-2 expression in Schwann cells is not restricted to CNS remyelination but is also expressed in a similar manner to SCIP/Oct-6 during Schwann cell myelination of neonatal peripheral nerves and regenerating transected adult nerve and in cultured Schwann cells following induction of elevated cAMP levels.

Animals↗
PubMed2005

Expression of POU-domain transcription factor, Oct-6, in schizophrenia, bipolar disorder and major depression.

BACKGROUND: The POU-domain transcription factor Oct-6 has been reported to be differentially expressed between schizophrenic and control post-mortem brains. In this study, we attempted to replicate this finding and to discover whether Oct-6 was also dysregulated in bipolar disorder and major depression. METHODS: Oct-6 mRNA and protein expression were determined by in-situ hybridization and immunohistochemistry respectively in sections of post-mortem brain. RESULTS: We did not observe any differences in Oct-6 expression between any of the groups under study. Oct-6 mRNA and protein was identically expressed in the hippocampal and cortical regions of most specimens in all groups, including controls. CONCLUSION: Oct-6 is, therefore, unlikely to be a specific marker for any psychological disorder; rather its expression in controls suggests that it is normally expressed in most adult brains.

Adult↗
PubMed2004

Discrete gene sets depend on POU domain transcription factor Brn3b/Brn-3.2/POU4f2 for their expression in the mouse embryonic retina.

Brn3b/Brn-3.2/POU4f2 is a POU domain transcription factor that is essential for retinal ganglion cell (RGC) differentiation, axonal outgrowth and survival. Our goal was to establish a link between Brn3b and the downstream events leading to RGC differentiation. We sought to determine both the number and types of genes that depend on Brn3b for their expression. RNA probes from wild-type and Brn3b(-/-) E14.5, E16.5 and E18.5 mouse retinas were hybridized to a microarray containing 18,816 retina-expressed cDNAs. At E14.5, we identified 87 genes whose expression was significantly altered in the absence of Brn3b and verified the results by real-time PCR and in situ hybridization. These genes fell into discrete sets that encoded transcription factors, proteins associated with neuron integrity and function, and secreted signaling molecules. We found that Brn3b influenced gene expression in non RGCs of the retina by controlling the expression of secreted signaling molecules such as sonic hedgehog and myostatin/Gdf8. At later developmental stages, additional alterations in gene expression were secondary consequences of aberrant RGC differentiation caused by the absence of Brn3b. Our results demonstrate that a small but crucial fraction of the RGC transcriptome is dependent on Brn3b. The Brn3b-dependent gene sets therefore provide a unique molecular signature for the developing retina.

Animals↗
PubMed2004

Developmental expression of the POU domain transcription factor Brn-3b (Pou4f2) in the lateral line and visual system of zebrafish.

Members of the class IV POU domain transcription factors are important regulators of neural development. In mouse, Brn-3b (Pou4f2, Brn3.2) and Brn-3c (Pou4f3, Brn3.1) are essential for the normal differentiation and maturation of retinal ganglion cells (RGCs) and hair cells of the auditory system, respectively. In this report, the cloning and expression profile of brn-3b in the zebrafish (Danio rerio) were assessed as the first step for understanding its role in the development of sensory systems. Two brn-3b alternative transcripts exhibited different onset of expression during development but shared overlapping expression domains in the adult visual system. The brn-3b expression in the zebrafish retina was consistent with a conserved role in differentiation and maintenance of RGCs. Expression was also observed in the optic tectum. Unexpectedly, brn-3b was prominently expressed in the migrating posterior lateral line primordium and larval neuromasts. For comparison, brn-3c expression was limited to the otic vesicle and was not detected in the lateral line during embryonic development. The expression of brn-3b in the mechanosensory lateral line of fish suggests a conserved function of a class IV POU domain transcription factor in sensory system development.

Amino Acid Sequence↗
PubMed1996

Function of the Drosophila POU domain transcription factor drifter as an upstream regulator of breathless receptor tyrosine kinase expression in developing trachea.

Organogenesis of the Drosophila tracheal system involves extensive directed cell migrations leading to a stereotypic series of interconnected tubules. Although numerous gene products have been shown to be essential for tracheal morphogenesis, direct functional relationships between participants have not been previously established. Both the breathless gene, encoding a Drosophila fibroblast growth factor receptor tyrosine kinase homologue, and the POU-domain transcription factor gene, drifter, are expressed in all tracheal cells and are essential for directed cell migrations. We demonstrate here that ubiquitously expressed Breathless protein under control of a heterologous heat-shock promoter is able to rescue the severely disrupted tracheal phenotype associated with drifter loss-of-function mutations. In the absence of Drifter function, breathless expression is initiated normally but transcript levels fall drastically to undetectable levels as tracheal differentiation proceeds. In addition, breathless regulatory DNA contains seven high affinity Drifter binding sites similar to previously identified Drifter recognition elements. These results suggest that the Drifter protein, which maintains its own expression through a tracheal-specific autoregulatory enhancer, is not necessary for initiation of breathless expression but functions as a direct transcriptional regulator necessary for maintenance of breathless transcripts at high levels during tracheal cell migration. This example of a mechanism for maintenance of a committed cell fate offers a model for understanding how essential gene activities can be maintained throughout organogenesis.

Animals↗
PubMed1996

Distinct variant DNA-binding sites determine cell-specific autoregulated expression of the Drosophila POU domain transcription factor drifter in midline glia or trachea.

Transcriptional regulators utilizing the POU domain DNA-binding motif have been shown to form multi-protein complexes dependent on the POU domain itself and its flexible recognition of various octamer sequence elements. We have identified two variant POU domain recognition elements DFRE1 and DFRE2, which are found within a 514-bp autoregulatory enhancer of the Drosophila melanogaster POU domain gene drifter (dfr). Both elements are capable of binding bacterially produced full-length DFR protein with high affinity, although they differ in the 5'-to-3' orientation of POU-specific and POU homeodomain subelements. When placed in dfr loss-of-function genetic backgrounds, all expression of dfr-lacZ fusion genes under control of the autoregulatory enhancer is dependent on DFR activity levels. However, the complete enhancer sequence directs beta-galactosidase expression in only a subset of cells which normally express the endogenous DFR protein, including the middle pair of midline glias of the ventral nerve cord, the oenocyte clusters, and all tracheal cells. In addition, DFRE1 and DFRE2 exhibit separable tissue-specific functions when independently disrupted or deleted. Disruption of DFRE1 function specifically abolishes beta-galactosidase expression in the middle pair of midline glias. Deletion of DFRE causes a specific loss of tracheal expression, leaving oenocyte and midline glia expression intact. These results suggest that dfr cell-specific autoregulation is determined by the context of DFR POU domain binding within the enhancer, which is possibly mediated by the formation of recognition element-specific heteromultimeric complexes containing additional tissue-specific factors.

Animals↗
PubMed1997

POU domain transcription factor brain 4 confers pancreatic alpha-cell-specific expression of the proglucagon gene through interaction with a novel proximal promoter G1 element.

The proglucagon gene is expressed in a highly restricted tissue-specific manner in the alpha cells of the pancreatic islet, the hypothalamus, and the small and large intestines. Proglucagon is processed to glucagon and glucagon-like peptides GLP-1 and -2. Glucagon is expressed in alpha cells and regulates glucose homeostasis. GLP-1 is implicated in the control of insulin secretion, food intake, and satiety signaling, and GLP-2 is implicated in regulating small-bowel growth. Cell-specific expression of the proglucagon gene is mediated by proteins that interact with the proximal G1 promoter element which contains several AT-rich domains with binding sites for homeodomain transcription factors. In an attempt to identify major homeodomain proteins involved in pancreatic alpha-cell-specific proglucagon expression, we found that the POU domain transcription factor brain 4 is abundantly expressed in proglucagon-producing islet cell lines and rat pancreatic islets. In the latter, brain 4 and glucagon immunoreactivity colocalize in the outer mantle of islets. Electrophoretic mobility shift assays with specific antisera identify brain 4 as a major constituent of nuclear proteins of glucagon-producing cells that bind to the G1 element of the proglucagon gene proximal promoter. Transcriptional transactivation experiments reveal that brain 4 is a major regulator of proglucagon gene expression by its interaction with the G1 element. The finding that a neuronal transcription factor is involved in glucagon gene transcription may explain the presence of proglucagon in certain areas of the brain as well as in pancreatic alpha cells. Further, this finding supports the idea that the neuronal properties of endodermis-derived endocrine pancreatic cells may find their basis in regulation of gene expression by neuronal transcription factors.

Animals↗
PubMed1990

A POU-domain transcription factor in early stem cells and germ cells of the mammalian embryo.

The murine oct-3 gene encodes a transcription factor containing a POU-specific domain and a homeodomain. In marked contrast to other homeodomain-encoding genes, oct-3 is expressed in the totipotent and pluripotent stem cells of the pregastrulation embryo and is down-regulated during differentiation to endoderm and mesoderm, suggesting that it has a role in early development. The oct-3 gene is also expressed in primordial germ cells and in the female germ line.

Amino Acid Sequence↗