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Results for “POU Domain Factors”

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PubMed1995

The POU domain transcription factor Brn-2: elevated expression in malignant melanoma and regulation of melanocyte-specific gene expression.

Previous work has shown that melanoma cell lines express a distinct octamer binding protein. Given the role of octamer-binding proteins in cell differentiation and development, the role this factor is a key issue in understanding melanocyte differentiation and transformation. Using a proteolytic clipping assay, we show that the melanoma-specific octamer factor is Brn-2/N-Oct3, a POU domain protein previously known to be expressed in adult brain and in the developing nervous system. N-Oct3 mRNA was detected in a range of human melanoma cell lines and was around 10-fold elevated compared to normal human melanocytes while mRNA for Brn-2 was also detected in a mouse melanoblast cell line. Expression of Brn-2/N-Oct3, in melanoma cells in cotransfection assays activated the expression of the MHC class II DR alpha promoter but repressed the activity of the melanocyte-specific tyrosinase promoter. Repression correlated with Brn-2/N-Oct3 binding in a mutually exclusive fashion with basic-helix-loop-helix-leucine-zipper (bHLH-LZ) transcription factor USF in vitro and with Brn-2 expression preventing activation of the tyrosinase promoter by the bHLH-LZ factor Microphthalmia in vivo. The potential role of Brn-2/N-Oct3 in melanocyte differentiation and gene expression is discussed.

Antigens, Neoplasm↗
PubMed1999

An octamer-binding site is crucial for the activity of an enhancer active at the embryonic met-/mesencephalic junction.

An enhancer sequence found in the Protease Nexin-1 (PN-1) gene was shown to drive lacZ expression specifically at the met-/mesencephalic junction in transgenic mouse embryos. A functional study of this enhancer has been performed to better understand the mechanisms regulating isthmic gene expression. An octamer-binding site for POU domain factors was found to be crucial for the activity of the enhancer in vivo. Comparative expression studies of POU domain factors, electrophoretic mobility shift assays and transient transfection experiments, strongly suggest that Brn-1/-2 regulate the enhancer activity in vivo. In addition, in vitro experiments indicated that FGF-8 was required for the maintenance of the enhancer activity, but not for the synthesis of Bn-1/-2. The data represents the first functional evidence for a role of POU factors in the regulation of met-/mesencephalic gene expression. It also implies that at least two regulatory pathways, namely the FGF-8 signaling and the octamer-binding site pathway, synergistically interact to control the PN-1 enhancer activity in vivo.

Amyloid beta-Protein Precursor↗
PubMed1995

drifter, a Drosophila POU-domain transcription factor, is required for correct differentiation and migration of tracheal cells and midline glia.

The Drosophila drifter (dfr) gene, previously referred to as Cf1a, encodes a POU-domain DNA-binding protein implicated as a neuron-specific regulator in the developing central nervous system (CNS). We have isolated full-length dfr cDNA clones that encode a 46-kD protein containing the conserved POU-domain DNA-binding domain. The use of alternate polyadenylation sites produces two dfr mRNA transcripts that are first expressed in stage 10 embryos at 5- to 6-hr of development. A specific anti-dfr polyclonal antiserum generated against a dfr-glutathione S-transferase fusion protein recognizes a 46-kD protein on Western blots and has been used to analyze the cell-specific distribution of dfr protein during embryonic development. dfr protein is distributed in a complex expression pattern including the tracheal system, the middle pair of midline glia, and selected CNS neurons. We have carried out a genetic characterization of the dfr locus, previously localized to region 65D of the third chromosome, by generating a series of overlapping deficiencies between 65A and 65E1 that were used to isolate dfrE82, an EMS-induced lethal allele. Analysis of dfrE82 mutant embryos shows a disruption of the developing tracheal tree as well as commissural defects in the developing CNS. Based on an examination of a cell-specific marker for tracheal cells and midline glia, these defects appear to be caused by a failure of these cells to follow their characteristic routes of migration. The dfrE82 tracheal phenotype is rescued by a dfr minigene present as a P-element transposon expressing wild-type dfr protein in tracheal cells. These results suggest that the dfr protein plays a fundamental role in the differentiation of tracheal cells and midline glia possibly by regulating the expression of essential cell-surface proteins required for cell-cell interactions involved in directed cell migrations.

Animals↗
PubMed2003

Expression of the POU domain transcription factor, Oct-6, is attenuated in the adult mouse telencephalon, but increased by neurotoxic damage.

Oct-6 is a POU III domain transcription factor expressed in embryonic stem cells, Schwann cells, and neuronal subpopulations during telencephalic development. Its role is unknown except in Schwann cells where it is thought to regulate myelin-specific gene expression. Expression of Oct-6 was recently discovered in neurons in postmortem human schizophrenic brain while being undetectable in matched controls. This study of human tissue contrasted in a number of regards with earlier studies of rodent brain and questioned what we can consider to be normal adult expression of this gene. In this study, we have investigated Oct-6 expression in normal adult mice and in mice treated with neuractive compounds. We show that Oct-6 is widely expressed in young adults but that its expression subsequently becomes restricted to specific neuronal subpopulations. Contrary to earlier reports, however, this specific expression is transient and is eventually completely lost from telencephalic neurons. The OCT-6 protein, somewhat surprisingly, is found to be cytoplasmic as well as nuclear in certain neuronal subpopulations. Finally, we report that neurotoxic doses of anticonvulsants reactivate OCT-6 expression in adult mouse brain.

Age Factors↗
PubMed1996

Disruption of mesectodermal lineages by temporal misexpression of the Drosophila POU-domain transcription factor, drifter.

Among the first cells to differentiate in the Drosophila ventral nerve cord, the mesectodermal (midline) lineage gives rise to a discrete set of neurons and glia previously demonstrated to play an important role in the organization of the developing nervous system. The relative simplicity of the midline has allowed the elucidation of many aspects of initial lineage commitment and subsequent differentiation. Based upon its mesectodermal expression pattern and loss-of-function phenotype, we have proposed a key role for the Drosophila POU-domain transcription factor, drifter (dfr), in mesectodermal lineage development. In this study, we have examined the developmental consequences of dfr misexpression using transgenic lines expressing wild-type Drifter protein under control of the heat-inducible hsp70 promoter. Induction of ubiquitous DFR protein during a restricted period of embryogenesis causes a defective axonal phenotype characterized by failure of commissure formation. Based on examination of cell-specific markers for mesectodermal cells, these defects appear to be the result of a suppression of single-minded expression resulting in the disruption of mesectodermal lineage designation and differentiation. The observed temporally restricted sensitivity to DFR expression suggests possible interactions between DFR protein and other stage-specific mesectodermal regulatory factors present before or after a defined mesectodermal developmental event.

Animals↗
PubMed2003

From lineage to wiring specificity. POU domain transcription factors control precise connections of Drosophila olfactory projection neurons.

Axonal selection of synaptic partners is generally believed to determine wiring specificity in the nervous system. However, we have recently found evidence for specific dendritic targeting in the olfactory system of Drosophila: second order olfactory neurons (Projection Neurons) from the anterodorsal (adPN) and lateral (lPN) lineages send their dendrites to stereotypical, intercalating but non-overlapping glomeruli. Here we show that POU domain transcription factors, Acj6 and Drifter, are expressed in adPNs and lPNs respectively, and are required for their dendritic targeting. Moreover, misexpression of Acj6 in lPNs, or Drifter in adPNs, results in dendritic targeting to glomeruli normally reserved for the other PN lineage. Thus, Acj6 and Drifter translate PN lineage information into distinct dendritic targeting specificity. Acj6 also controls stereotypical axon terminal arborization of PNs in a central target, suggesting that the connectivity of PN axons and dendrites in different brain centers is coordinately regulated.

Animals↗
PubMed2006

Regulation of NF-kappaB-dependent gene expression by the POU domain transcription factor Oct-1.

Maintenance of the cells of the vessel wall in a quiescent state is an important aspect of normal vascular physiology. Transcriptional repressors are widely believed to regulate this process, yet the exact factors involved and the mechanism of repression are not known. Here, we report that the POU domain transcription factor Oct-1 represses the expression of E-selectin and vascular cell adhesion molecule (VCAM-1), two cytokine-inducible, NF-kappaB-dependent endothelial-leukocyte adhesion molecules that participate in the leukocyte recruitment phase of the inflammatory response. Co-transfection and microinjection studies demonstrate that Oct-1 blocks tumor necrosis factor alpha-stimulated E-selectin and VCAM-1 expression. Gene expression arrays indicate that control of tumor necrosis factor alpha-induced, NF-kappaB-dependent gene expression by Oct-1 is promoter-specific. A DNA-binding mutant of Oct-1 represses NF-kappaB-dependent reporter gene expression. Biochemically, Oct-1 interacts with p65, suggesting that Oct-1 is involved in the regulation of NF-kappaB transactivation function. NF-kappaB-dependent gene expression is more pronounced in Oct-1-deficient than in wild-type murine embryonic fibroblasts, and reintroduction of human Oct-1 abolishes these differences. Finally, the cytokine interleukin-6 induces Oct-1 gene expression, providing a biologically relevant means by which NF-kappaB-dependent gene expression can be selectively reverted by Oct-1 to quiescent levels.

3T3 Cells↗
PubMed1999

The odor specificities of a subset of olfactory receptor neurons are governed by Acj6, a POU-domain transcription factor.

Little is known about how the odor specificities of olfactory neurons are generated, a process essential to olfactory coding. We have found that neuronal identity relies on the abnormal chemosensory jump 6 (acj6) gene, originally identified by a defect in olfactory behavior. Physiological analysis of individual olfactory neurons shows that in acj6 mutants, a subset of neurons acquires a different odorant response profile. Certain other neurons do not respond to any tested odors in acj6. Molecular analysis of acj6 shows that it encodes a POU-domain transcription factor expressed in olfactory neurons. Our data suggest that the odor response spectrum of an olfactory neuron, and perhaps the choice of receptor genes, is determined through a process requiring the action of Acj6.

Alleles↗
PubMed2002

Identification of genes that are downregulated in the absence of the POU domain transcription factor pou3f1 (Oct-6, Tst-1, SCIP) in sciatic nerve.

Despite the importance of myelinating Schwann cells in health and disease, little is known about the genetic mechanisms underlying their development. The POU domain transcription factor pou3f1 (Tst-1, SCIP, Oct-6) is required for the normal differentiation of myelinating Schwann cells, but its precise role requires identification of the genes that it regulates. Here we report the isolation of six genes whose expression is reduced in the absence of pou3f1. Only one of these genes, the fatty acid transport protein P2, was known previously to be expressed in Schwann cells. The LIM domain proteins cysteine-rich protein-1 (CRP1) and CRP2 are expressed in sciatic nerve and induced by forskolin in cultured Schwann cells, but only CRP2 requires pou3f1 for normal expression. pou3f1 appears to require the claw paw gene product for activation of at least some of its downstream effector genes. Expression of the novel Schwann cell genes after nerve injury suggests that they are myelin related. One of the genes, tramdorin1, encodes a novel amino acid transport protein that is localized to paranodes and incisures. Our results suggest that pou3f1 functions to activate gene expression in the differentiation of myelinating Schwann cells.

Adaptor Proteins, Signal Transducing↗
PubMed1993

cDNA cloning of human N-Oct3, a nervous-system specific POU domain transcription factor binding to the octamer DNA motif.

Octamer transcription factors (Oct or OTF) are a subset of the POU family of transcription factors which regulate transcription of cellular and viral genes by binding to the octamer sequence motif ATGCAAAT. Neurons and astroglial cells harbour, in addition to the ubiquitous Oct 1 factor, at least four specific factors termed N-Oct 2,3,4 and 5. Here we report the cloning of a human brain-derived cDNA that encodes the N-Oct 3 protein (443 aa) which is the human counterpart of the murine brain-2 gene product. Extracts from mammalian cells transfected with an N-Oct 3 expression vector yield three octamer DNA binding complexes in the electrophoretic mobility shift assay (EMSA): N-Oct 3 and two smaller complexes comigrating with the N-Oct 5A and 5B proteins of brain extracts. We present data suggesting that the N-Oct 5A and 5B proteins are generated by alternative translation initiation at internal AUG residues which are located before the POU domain. In contrast to the putative N-Oct 5 proteins, which are transcriptionally inert, the N-Oct 3 protein activates transcription from a reporter gene promoter with an octamer sequence, when transiently expressed in HeLa cells.

Amino Acid Sequence↗
PubMed1996

Expression of the gene for the POU domain transcription factor Tst-1/Oct6 is regulated by an estrogen-dependent enhancer.

Expression of the POU domain protein Tst-1/Oct6 during development of glia and neurons is subject to a tight multifactorial control. Here we show that 17beta-estradiol increases the level of endogenous Tst-1/Oct6 in glial cells. This effect was mediated at the level of gene expression by an enhancer present in the 5' flanking region of the mouse gene for Tst-1/Oct6, approximately 5 kb upstream of the transcriptional start site. The enhancer contained as the functional element a sequence motif that closely resembled a classical estrogen response element. It consisted of an imperfect palindrome with a spacing of 3 bp, and was bound in vitro by activated estrogen receptor. Furthermore, this element was able to confer estrogen responsiveness when introduced into a heterologous promoter. In the Tst-1/Oct6 gene enhancer, a TPA response element was found in close proximity to the estrogen receptor binding site. As a consequence, TPA and estrogen activated transcription of the Tst-1/Oct6 gene in a synergistic manner.

Animals↗
PubMed2001

The Ath5 proneural genes function upstream of Brn3 POU domain transcription factor genes to promote retinal ganglion cell development.

During retinogenesis, the Xenopus basic helix-loop-helix transcription factor Xath5 has been shown to promote a ganglion cell fate. In the developing mouse and chicken retinas, gene targeting and overexpression studies have demonstrated critical roles for the Brn3 POU domain transcription factor genes in the promotion of ganglion cell differentiation. However, the genetic relationship between Ath5 and Brn3 genes is unknown. To understand the genetic regulatory network(s) that controls retinal ganglion cell development, we analyzed the relationship between Ath5 and Brn3 genes by using a gain-of-function approach in the chicken embryo. We found that during retinogenesis, the chicken Ath5 gene (Cath5) is expressed in retinal progenitors and in differentiating ganglion cells but is absent in terminally differentiated ganglion cells. Forced expression of both Cath5 and the mouse Ath5 gene (Math5) in retinal progenitors activates the expression of cBrn3c following central-to-peripheral and temporal-to-nasal gradients. As a result, similar to the Xath5 protein, both Cath5 and Math5 proteins have the ability to promote the development of ganglion cells. Moreover, we found that forced expression of all three Brn3 genes also can stimulate the expression of cBrn3c. We further found that Ath5 and Brn3 proteins are capable of transactivating a Brn3b promoter. Thus, these data suggest that the expression of cBrn3c in the chicken and Brn3b in the mouse is initially activated by Ath5 factors in newly generated ganglion cells and later maintained by a feedback loop of Brn3 factors in the differentiated ganglion cells.

Animals↗
PubMed1995

The POU domain transcription factor Brn-2 is required for the determination of specific neuronal lineages in the hypothalamus of the mouse.

We generated mice carrying a loss-of-function mutation in Brn-2, a gene encoding a nervous system specific POU transcription factor, by gene targeting in embryonic stem cells. In homozygous mutant embryos, migratory precursor cells for neurons of the paraventricular nuclei (PVN) and the supraoptic nuclei (SO) of the hypothalamus die at approximately E12.5. All homozygous mutants suffered mortality within 10 days after birth, possibly because of a complete deficiency of these neurons in the hypothalamus. Although neither developmental nor histological abnormalities were observed in heterozygous mice, the levels of expression of vasopressin and oxytocin in the hypothalamus of these animals were half these of wild-type mice. These results strongly suggest that Brn-2 plays an essential role in the determination and development of the PVN and SO neuronal lineages in the hypothalamus.

Animals↗
PubMed1993

Regulation of JC virus by the POU-domain transcription factor Tst-1: implications for progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy results from an opportunistic infection of myelin-producing oligodendrocytes by the glia-specific human papovavirus JC. In this report, evidence is presented that the glial transcription factor Tst-1, a member of the POU-domain family, stimulates transcription of both early and late viral genes. Stimulation was dependent on site-specific binding of Tst-1 to the JC viral regulatory region and on the presence of an intact amino-terminal transactivation domain within Tst-1. Because of its ability to increase the expression of viral large tumor antigen, Tst-1 stimulated viral DNA replication, without participating directly in the replication event. Our results suggest that Tst-1 is one of the determining factors in the glia specificity of JC virus.

Base Sequence↗
PubMed2002

The C. elegans POU-domain transcription factor UNC-86 regulates the tph-1 tryptophan hydroxylase gene and neurite outgrowth in specific serotonergic neurons.

A fundamental question in developmental neurobiology is how a common neurotransmitter is specified in different neuronal types?. We describe cell-specific regulation of the serotonergic phenotype by the C. elegans POU-transcription factor UNC-86. We show that unc-86 regulates particular aspects of the terminal neuronal identity in four classes of serotonergic neurons, but that the development of the ADF serotonergic neurons is regulated by an UNC-86-independent program. In the NSM neurons, the role of unc-86 is confined in late differentiation; the neurons are generated but do not express genes necessary for serotonergic neurotransmission. unc-86-null mutations affect the expression in NSM of tph-1, which encodes the serotonin synthetic enzyme tryptophan hydroxylase, and cat-1, which encodes a vesicular transporter that loads serotonin into synaptic vesicles, suggesting that unc-86 coordinately regulates serotonin synthesis and packaging. However, unc-86-null mutations do not impair the ability of NSM to reuptake serotonin released from the ADF serotonergic chemosensory neurons and this serotonin reuptake is sensitive to the serotonin reuptake block drugs imipramine and fluoxetine, demonstrating that serotonin synthesis and reuptake is regulated by distinct factors. The NSM neurons in unc-86-null mutants also display abnormal neurite outgrowth, suggesting a role of unc-86 in regulating this process as well.

Animals↗