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Results for “POU Domain Factors”

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PubMed1993

A novel Brn3-like POU transcription factor expressed in subsets of rat sensory and spinal cord neurons.

Brn3a and Brn3b are mammalian members of the POU class of transcription factors. They are closely related to each other and to Unc86, which determines the normal development of certain cells, including mechanoreceptive sensory neurons in Caenorhabditis elegans. We screened a rat dorsal root ganglion (DRG) cDNA library at moderate stringency with a Brn3a POU-domain probe and identified a novel transcript encoding a POU protein that we have named Brn3c. Brn3c closely resembles Brn3a and Brn3b in its POU-domain and thus helps define a family of Unc86-related mammalian POU factors. Both Brn3a and Brn3c are expressed only in the central and peripheral nervous systems. In the neonatal rat, northern blots revealed a 3.6 kb Brn3a transcript in DRG, spinal cord and hindbrain, and a 2.6 kb Brn3c transcript in DRG and spinal cord. In situ hybridization showed that most DRG neurons express Brn3a whereas only a small subset of neurons expresses Brn3c. In the spinal cord, Brn3a is expressed by many dorsal horn neurons. In contrast, Brn3c is expressed by a very small number of cells in laminae 4/5 of the dorsal horn. These data suggest that Brn3-related POU factors may be involved in the development or function of particular subclasses of sensory and spinal cord neurons.

Amino Acid Sequence↗

PubMed1996

Regulation of human involucrin promoter activity by POU domain proteins.

POU domain transcription factors are expressed in the epidermis and are thought to be important regulators of keratinocyte gene expression. In the present article we demonstrate that POU transcription factors suppress transcription of the human involucrin (hINV) promoter. Cotransfection of pINV-2473, a construct containing 2473 base pairs of hINV upstream sequence linked to luciferase, with POU homeodomain transcription factors Oct1, Oct2, Brn4, SCIP, Skn1a or Skn1i, results in a strong suppression of basal promoter activity. The hINV upstream region includes a consensus POU transcription factor binding site, 5'-ATGCAAAT-3', centered around nucleotide -1277. Although this site interacts with POU factors, assays of promoter activity for a series of progressive 5' end truncations demonstrate that this site is not required for POU factor-dependent transcriptional suppression. Suppression is observed with the shortest truncation construct tested, pINV-41, suggesting that this inhibition may be mediated by effects on TATA box proteins. SCIP mutants that lack transactivation or DNA binding domains were shown to suppress transcription, suggesting that the DNA binding and transactivation domains are not required for suppression. Moreover, cotransfection of the pINV-2473 with pKSM13(+)OCT, which contains a single consensus OCT binding site, results in an increase in basal promoter activity, suggesting that endogenous POU factors suppress hINV promoter activity. In addition to inhibiting basal transcription, POU transcription factors also suppress phorbol ester-stimulated hINV promoter activity. These studies suggest that suppression of hINV promoter activity does not require the amino-terminal segment of the POU factor or direct POU factor interaction with DNA and suggest that the suppression may be via indirect interaction with other proteins in the vicinity of the TATA box. Thus, involucrin joins the ranks of a small set of genes that are regulated by POU factors in an octamer binding site-independent manner.

Base Sequence↗

PubMed1991

Oct-3 is a maternal factor required for the first mouse embryonic division.

Oct-3 is a POU domain transcription factor that binds the octamer DNA motif and is present in mouse oocytes before and after fertilization. When fertilized oocytes were injected with antisense Oct-3 oligonucleotides or double-stranded DNA containing the octamer motif, embryonic DNA synthesis was inhibited and the embryos were arrested at the one-cell stage. In vitro synthesized Oct-3 mRNA rescued the developmental block induced by antisense Oct-3 oligonucleotide. We conclude that maternally inherited Oct-3 is required for DNA replication and division of the one-cell embryo.

Animals↗

PubMed2016

Substituting mouse transcription factor Pou4f2 with a sea urchin orthologue restores retinal ganglion cell development.

Pou domain transcription factor Pou4f2 is essential for the development of retinal ganglion cells (RGCs) in the vertebrate retina. A distant orthologue of Pou4f2 exists in the genome of the sea urchin (class Echinoidea) Strongylocentrotus purpuratus (SpPou4f1/2), yet the photosensory structure of sea urchins is strikingly different from that of the mammalian retina. Sea urchins have no obvious eyes, but have photoreceptors clustered around their tube feet disc. The mechanisms that are associated with the development and function of photoreception in sea urchins are largely unexplored. As an initial approach to better understand the sea urchin photosensory structure and relate it to the mammalian retina, we asked whether SpPou4f1/2 could support RGC development in the absence of Pou4f2. To answer this question, we replaced genomic Pou4f2 with an SpPou4f1/2 cDNA. In Pou4f2-null mice, retinas expressing SpPou4f1/2 were outwardly identical to those of wild-type mice. SpPou4f1/2 retinas exhibited dark-adapted electroretinogram scotopic threshold responses, indicating functionally active RGCs. During retinal development, SpPou4f1/2 activated RGC-specific genes and in S. purpuratus, SpPou4f2 was expressed in photoreceptor cells of tube feet in a pattern distinct from Opsin4 and Pax6. Our results suggest that SpPou4f1/2 and Pou4f2 share conserved components of a gene network for photosensory development and they maintain their conserved intrinsic functions despite vast morphological differences in mouse and sea urchin photosensory structures.

Animals↗

PubMed2006

Regulation of neuroblast competence: multiple temporal identity factors specify distinct neuronal fates within a single early competence window.

Cellular competence is an essential but poorly understood aspect of development. Is competence a general property that affects multiple signaling pathways (e.g., chromatin state), or is competence specific for each signaling pathway (e.g., availability of cofactors)? Here we find that Drosophila neuroblast 7-1 (NB7-1) has a single early window of competence to respond to four different temporal identity genes (Hunchback, Krüppel, Pdm, and Castor); that each of these factors specifies distinct motor neuron identities within this competence window but not outside it; and that progressive restriction to respond to Hunchback and Krüppel occurs within this window. Our work raises the possibility that multiple competence windows may allow the same factors to generate different cell types within the same lineage.

Animals↗

PubMed1992

Down-regulation of the POU transcription factor SCIP is an early event in oligodendrocyte differentiation in vitro.

The POU-domain transcription factor SCIP (also known as Tst-1) has been implicated in the development of Schwann cells, the myelinating cells of the peripheral nervous system (PNS). We have investigated the possibility that SCIP also might play a role in the development of oligodendrocytes, the myelinating cells of the central nervous system (CNS). We purified oligodendrocyte precursors (O-2A progenitors) by immunoselection and cultured them in the presence of platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), which together keep O-2A progenitors proliferating and prevent oligodendrocyte differentiation. Under these culture conditions, O-2A progenitors expressed high levels of SCIP mRNA and protein, and did not express myelin-specific genes. When oligodendrocyte differentiation was initiated by withdrawing the growth factors, SCIP mRNA was rapidly down-regulated, followed by a decline in SCIP protein and the sequential activation of myelin-specific genes. Rapid down-regulation of SCIP mRNA required continued protein synthesis. In O-2A progenitors that were cultured in the presence of PDGF alone, SCIP expression declined to an intermediate level, and low levels of the myelin gene products were induced. Thus, the level of SCIP expression in O-2A progenitors is inversely related to the level of myelin gene expression, suggesting that SCIP may be involved in the developmental switch from proliferation to differentiation in the oligodendrocyte lineage. When O-2A progenitors are cultured in the presence of 10% fetal calf serum, they differentiate into type-2 astrocytes rather than oligodendrocytes. SCIP mRNA was also down-regulated in type-2 astrocytes, which do not express myelin genes, so down-regulation of SCIP seems to be more closely linked to the cessation of cell proliferation per se than the expression of a particular differentiated phenotype.

Animals↗

PubMed1995

Nerve growth factor-regulated properties of sensory neurones in Oct-2 null mutant mice.

The POU-domain transcription factor Oct-2 is expressed in both B lymphocytes and sensory neurones, where its expression is regulated by nerve growth factor (NGF). In order to define a possible role for Oct-2 in neurotrophin signalling, we examined the expression of an NGF-regulated channel (capsaicin-evoked ion fluxes), neuropeptides (substance P, calcitonin gene-related peptide), structural proteins (neurofilaments and peripherin) and receptors (trks) in dorsal root ganglion neurones derived from perinatal transgenic mice containing a defective Oct-2 structural gene. Northern blots show that central nervous tissue contains a larger than normal (> 10 kb) mRNA transcript corresponding in size to an Oct-2 transcript encoding a defective protein. PCR analysis shows the absence of normal Oct-2 transcripts in dorsal root ganglia. In null mutants, capsaicin sensitivity, and neuropeptide and cytoskeletal protein expression were unaffected by the loss of Oct-2 expression. The number of sensory neurones and the gross morphology of CNS tissues that normally express high levels of Oct-2 were also examined and found to be normal in the null mutant. Heterozygous animals show normal thresholds of sensitivity to noxious heat and normal inflammatory responses. Oct-2 does not therefore play an essential role in the NGF responsiveness of sensory neurones in these animals.

Animals↗

PubMed2003

Requirement for a nuclear function of beta-catenin in Wnt signaling.

Wnt signaling stabilizes beta-catenin, which in turn influences the transcription of Wnt-responsive genes in conjunction with T-cell factor (TCF) transcription factors. At present, there are two models for the actions of beta-catenin. The conventional nuclear model suggests that beta-catenin acts in the nucleus to form a heterodimeric transcriptional factor complex with TCF, with TCF providing DNA-specific binding and the C and N termini of beta-catenin stimulating transcription. The alternative cytoplasmic model postulates that beta-catenin exports TCF from the nucleus to relieve its repressive activity or activates it in the cytoplasm. We have generated modified forms of beta-catenin and used RNA interference against endogenous beta-catenin to distinguish between these models in cultured mammalian and Drosophila cells. We show that the VP16 transcriptional activation domain can replace the C terminus of beta-catenin without loss of function and that the function of beta-catenin is compromised by fusion to a transcriptional repressor domain from histone deacetylase, favoring the direct effects of beta-catenin in the nucleus. Furthermore, membrane-tethered beta-catenin requires interaction with the adenomatous polyposis coli protein but not with TCF for its function, whereas untethered beta-catenin requires binding to TCF for its signaling activity. Importantly, by using RNA interference, we show that the signaling activity of membrane-tethered beta-catenin, but not free beta-catenin, requires the presence of endogenous beta-catenin, which is able to accumulate in the nucleus when stabilized by the binding of the beta-catenin degradation machinery to the membrane-tethered form. All of these data support a nuclear model for the normal function of beta-catenin.

Animals↗

PubMed1996

Crystallization and preliminary X-ray analysis of Pit-1 POU domain complexed to a 28 base pair DNA element.

The POU domain, representing an approximately 150 amino acid conserved region, serves as the DNA-recognition domain for a large number of eukaryotic transcription factors. Bipartite in nature, the POU domain is comprised of a N-terminal POU-specific domain connected by a linker of variable length to a C-terminal homeodomain. We report here co-crystals of pituitary-specific factor Pit-1 POU domain bound as a dimer to a 28 bp DNA fragment. The crystals diffract to at least 2.3 angstroms in resolution and belong to space group P1 with unit cell dimensions of a = 42.5 angstroms, b = 50.1 angstroms, c = 55.8 angstroms, alpha = 76.7 degrees, beta = 79.3 degrees, and gamma = 67.2 degrees.

Base Sequence↗

PubMed1998

Potassium chloride inhibits proliferation of cerebellar granule neuron progenitors.

CNS neurogenesis involves a critical transition where neuronal progenitors exit the cell cycle and initiate terminal differentiation. Recent experiments have suggested that depolarization inhibits DNA synthesis in cortical progenitors. Depolarization of proliferating neuronal progenitors may thus activate mechanisms that prevent proliferation and allow the initiation of terminal differentiation. We present evidence that depolarizing concentrations of KCl (25-50 mM) reduce proliferation of developing postnatal cerebellar granule cells in culture. These studies show that KCl antagonizes the mitogenic response of granule cells to insulin-like growth factor-I (IGF-I) and that this reduction in proliferating cells is not the result of a selective cell death. We also examined the differentiation of granule cell cultures using Brn-5 expression as an early differentiation marker. In vivo Brn-5 expression occurs soon after developing granule cells exit the cell cycle and begin their final differentiation. In control cultures and cultures treated with high concentrations of KCl Brn-5 expression increased over 24-48 h of culture. Our results suggest depolarizing concentrations of KCl antagonize proliferation of cerebellar granule neuron progenitors however allow their continued differentiation.

Animals↗

PubMedDate not supplied

[Spliced oct-1 gene mRNA isoforms with untranslated exons and a deletion in the region coding for the POU-specific domain].

Transcription factor Oct-1 is involved in expression regulation of housekeeping genes, in lymphocyte differentiation, and in the immune response. Tissue-specific oct-1 mRNA isoforms are known to be expressed in lymphoid cells. Four new mouse isoforms were identified. Of these, two were tissue-specific (oct-1R alpha and oct-1R beta) and contained exon 1L. The oct-1R alpha was shown to contain an additional fragment, which corresponds to an exon located in the 3'-region of mouse otf-1. No homolog was found in human OTF-1. The oct-1R alpha isoform proved to lack an exon coding for a fragment of the POU domain. This deletion results in a loss of the first helix of the domain, and the mutant protein is devoid of affinity for octamer ATGCAAAT. Two other mRNA isoforms, oct-1d and oct-1e, were shown to contain untranslated regions between exons 1U and 2. The regions correspond to exons 1i and 2i located between exons 1U and 1L in the 5'-region of the mouse oct-1 gene. Human OTF-1 was not found to contain exon 1i. On evidence of these and published data, it was assumed that a set of oct-1 isoforms is present in the cell, reflecting the complexity of expression regulation of oct-1 and the multiplicity of its functions.

5' Untranslated Regions↗

PubMed1998

The Drosophila SOX-domain protein Dichaete is required for the development of the central nervous system midline.

SOX-domain proteins are a class of developmentally important transcriptional regulators related to the mammalian testis determining factor SRY. In common with other SOX-domain genes, the Drosophila Dichaete gene has a dynamic expression profile in the developing central nervous system, including cells of the ventral midline. We find defects in the differentiation of midline glia and concomitant axonal defects in Dichaete mutants that are rescued by driving Dichaete expression in the midline. Since Dichaete is required for the correct specification or differentiation of midline glia, we have used the ventral midline as a model system to study SOX gene function in vivo and demonstrate a genetic interaction between Dichaete and the POU domain gene ventral veinless. In mammals, a protein related to Dichaete, SOX2, also interacts with POU transcription factors. The midline phenotypes of Dichaete mutations are rescued by expression of mouse SOX2. Our data suggest that SOX gene structure, function and interactions have been conserved during evolution.

Alleles↗

PubMed1992

The Oct-1 POU domain mediates interactions between Oct-1 and other POU proteins.

The POU domain is the conserved DNA binding domain of a family of gene regulatory proteins. It consists of a POU-specific domain and a POU homeodomain, connected by a variable linker region. Oct-1 is a ubiquitously expressed POU domain transcription factor. It binds to the canonical octamer sequence (ATGCAAAT) as a monomer. Here we show by chemical cross-linking and protein affinity chromatography that the Oct-1 POU domain monomers can interact in solution. This association requires both the POU homeodomain and the POU-specific domain. The interaction is transient in solution and can be stabilized by binding to the heptamer-octamer sequence in the immunoglobulin heavy-chain promoter. This correlates with cooperative DNA binding to this site. POU proteins from different subclasses, including Oct-1, Oct-2A, Oct-6, and a chimeric Oct-1 protein containing the Pit-1 POU domain, can bind cooperatively to a double binding site and form a heteromeric complex.

Base Sequence↗

PubMed2000

The BRN-3A transcription factor protects sensory but not sympathetic neurons from programmed cell death/apoptosis.

Inactivation of the gene encoding the POU domain transcription factor BRN-3A results in the absence of specific neurons in knockout mice. Here we demonstrate for the first time a direct effect of BRN-3A on the survival of neuronal cells. Specifically, overexpression of BRN-3A in cultured trigeminal ganglion or dorsal root ganglion sensory neurons enhanced their survival following the withdrawal of nerve growth factor. Moreover, reduction of BRN-3A levels impaired the survival of these neurons. The survival of sympathetic neurons was not affected by either approach. Similarly, overexpression of BRN-3A activated the endogenous Bcl-2 gene in trigeminal neurons, but not in sympathetic neurons. The protective effect of BRN-3A on trigeminal neuron survival following nerve growth factor withdrawal significantly increased during embryonic development. In contrast, overexpression of the related factor BRN-3B enhanced survival of trigeminal neurons only at an early stage of embryonic development. Thus, BRN-3A (and in some circumstances, BRN-3B) can promote the survival of nerve growth factor-dependent sensory but not sympathetic neurons, allowing it to play a direct role in the survival of some (but not all) neuronal populations in the developing and adult nervous systems.

Animals↗

PubMed2004

Hox/Pbx and Brn binding sites mediate Pax3 expression in vitro and in vivo.

Pax3 is a paired-homeodomain class transcription factor that serves a role in dorsal-ventral and medial-lateral patterning during vertebrate embryogenesis. Its expression is localized to dorsal domains within the developing neural tube and lateral domains within the developing somite. Additionally, modulation of its expression occurs along the rostral-caudal axis. Previous studies [Development 124 (1997) 617] have localized sequence elements required for expression of Pax3 in the neural tube and neural crest to a 1.6 kbp promoter fragment. In the present study, four discrete DNA elements within the 1.6 kbp promoter fragment are shown by electrophoretic mobility shift assays (EMSA) to exhibit sequence specific interactions with proteins present in nuclear extracts from P19 EC cells induced to express Pax3 by treatment with retinoic acid (RA). Proteins interacting at each of these elements are identified based on biochemical purification using DNA affinity chromatography or a candidate approach. These identifications were confirmed by the ability of specific antibodies to super-shift DNA-protein complexes in EMSA. Two of the four DNA sequence elements are shown to interact with the neural specific Pou-domain class III transcription factors Brn1 and Brn2. The remaining sites contain either consensus binding elements for heterodimers of Pbx and an anterior set of Hox family members, from paralogous groups 1-5, or monomeric Meis and are shown to interact with members of the Pbx and Meis families. Ectopic expression of Brn2 plus HoxA1 but not either factor alone, is sufficient to induce efficient expression from the endogenous Pax3 promoter in P19 EC stem cells under conditions where they would not otherwise express Pax3. Finally, in transgenic mice, mutation of either of the Pou-domain protein binding sites results in reduced expression throughout the neural tube while mutation of the Pbx/Hox binding site results in loss of expression in the anterior domain in which Hox family members from paralogous groups 1-5 are expressed. These observations demonstrate that binding elements for both neural and anterior-posterior position specific transcription factors mediate domains of Pax3 expression.

Animals↗

PubMed1999

A role for the POU-III transcription factor Brn-4 in the regulation of striatal neuron precursor differentiation.

Both insulin-like growth factor-I (IGF-I) and brain-derived neurotrophic factor (BDNF) induce the differentiation of post-mitotic neuronal precursors, derived from embryonic day 14 (E14) mouse striatal multipotent stem cells. Here we ask whether this differentiation is mediated by a member of the POU-III class of neural transcription factors. Exposure of stem cell progeny to either IGF-I or BDNF resulted in a rapid upregulation of Brn-4 mRNA and protein. Indirect immunocytochemistry with Brn-4 antiserum showed that the protein was expressed in newly generated neurons. Other POU-III genes, such as Brn-1 and Brn-2, did not exhibit this upregulation. Basic FGF, a mitogen for these neuronal precursors, did not stimulate Brn-4 expression. In the E14 mouse striatum, Brn-4-immunoreactive cells formed a boundary between the nestin-immunoreactive cells of the ventricular zone and the beta-tubulin-immunoreactive neurons migrating into the mantle zone. Loss of Brn-4 function during the differentiation of stem cell-derived or primary E14 striatal neuron precursors, by inclusion of antisense oligonucleotides, caused a reduction in the number of beta-tubulin-immunoreactive neurons. These findings suggest that Brn-4 mediates, at least in part, the actions of epigenetic signals that induce striatal neuron-precursor differentiation.

Animals↗

PubMed2004

Computational identification of developmental enhancers: conservation and function of transcription factor binding-site clusters in Drosophila melanogaster and Drosophila pseudoobscura.

BACKGROUND: The identification of sequences that control transcription in metazoans is a major goal of genome analysis. In a previous study, we demonstrated that searching for clusters of predicted transcription factor binding sites could discover active regulatory sequences, and identified 37 regions of the Drosophila melanogaster genome with high densities of predicted binding sites for five transcription factors involved in anterior-posterior embryonic patterning. Nine of these clusters overlapped known enhancers. Here, we report the results of in vivo functional analysis of 27 remaining clusters. RESULTS: We generated transgenic flies carrying each cluster attached to a basal promoter and reporter gene, and assayed embryos for reporter gene expression. Six clusters are enhancers of adjacent genes: giant, fushi tarazu, odd-skipped, nubbin, squeeze and pdm2; three drive expression in patterns unrelated to those of neighboring genes; the remaining 18 do not appear to have enhancer activity. We used the Drosophila pseudoobscura genome to compare patterns of evolution in and around the 15 positive and 18 false-positive predictions. Although conservation of primary sequence cannot distinguish true from false positives, conservation of binding-site clustering accurately discriminates functional binding-site clusters from those with no function. We incorporated conservation of binding-site clustering into a new genome-wide enhancer screen, and predict several hundred new regulatory sequences, including 85 adjacent to genes with embryonic patterns. CONCLUSIONS: Measuring conservation of sequence features closely linked to function--such as binding-site clusterin--makes better use of comparative sequence data than commonly used methods that examine only sequence identity.

Animals↗

PubMed1999

Neurons differentiating from murine neural crest in culture exhibit sensory or sympathetic-like calcium currents.

The trunk neural crest gives rise to peripheral sensory and sympathetic neurons. In culture, neural crest cells can be induced to differentiate into either neuronal phenotype. Few studies have examined the differentiation of physiological properties in cultures of neural crest cells. Using whole-cell recordings, our study examined the effects of growth factors on high-voltage-activated calcium current profiles exhibited by neurons differentiating in culture. We compared these profiles with those exhibited by sensory and sympathetic neurons. Neural crest cells in culture gave rise to neurons with calcium current profiles identical to either sensory or sympathetic neurons, depending on the growth conditions. On average, the calcium current profile for sensory neurons was 23% (L), 51% (N), and 12% (P), while sympathetic neurons had a similar L-type current (20%), higher N-type (76%), and lower P-type (4%). Neural crest cells cultured with human leukemia inhibitory factor plus somite cells produced neurons with a sympathetic-like calcium current profile (L: 17%, N: 75%, and P: 4%). However, murine leukemia inhibitory factor (L: 25%, N: 52%, and P: 13%) and ciliary neurotrophic factor (L: 18%, N: 49%, and P: 9%) plus somite cells produced neurons with sensory-like calcium current profiles. These growth conditions did not modify the calcium current profiles of neurons cultured from embryonic and neonatal ganglia. Similarly, murine leukemia inhibitory factor produced a greater percentage of neurons (57%) with sensitivity to capsaicin (sensory phenotype) than human leukemia inhibitory factor (3%). Physiological traits can be a useful tool for the determination of neuronal phenotype in culture where other traits may be less stable.

Animals↗