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Results for “POU Domain Factors”

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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↗

PubMed1996

Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons.

Specific families of transcription factors mediate events in the sequential maturation of distinct neuronal phenotypes. Members of one such family, the class IV POU domain transcription factor Brn-3.0, and two highly related factors Brn-3.1 and Brn-3.2, are differentially expressed in the developing and mature mammalian nervous system. The expression pattern of Brn-3.0 suggested that it has an important role in the development of sensory ganglia, as well as red nucleus, inferior olive, and nucleus ambiguus. Analysis of mice null for the Brn-3.0 locus shows that Brn-3.0 is required for the survival of subpopulations of proprioceptive, mechanoreceptive and nociceptive sensory neurons, where deletion of the gene affects neurotrophin and neurotrophin-receptor gene expression. Deletion of Brn-3.0 also alters either differentiation, migration or survival of specific central neuronal populations.

Animals↗

PubMed1992

Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia.

A point mutation in the POU-specific portion of the human gene that encodes the tissue-specific POU-domain transcription factor, Pit-1, results in hypopituitarism, with deficiencies of growth hormone, prolactin, and thyroid-stimulating hormone. In two unrelated Dutch families, a mutation in Pit-1 that altered an alanine in the first putative alpha helix of the POU-specific domain to proline was observed. This mutation generated a protein capable of binding to DNA response elements but unable to effectively activate its known target genes, growth hormone and prolactin. The phenotype of the affected individuals suggests that the mutant Pit-1 protein is competent to initiate other programs of gene activation required for normal proliferation of somatotrope, lactotrope, and thyrotrope cell types. Thus, a mutation in the POU-specific domain of Pit-1 has a selective effect on a subset of Pit-1 target genes.

Animals↗

PubMedDate not supplied

Pit-1-dependent expression of the receptor for growth hormone releasing factor mediates pituitary cell growth.

In Snell (dw) and Jackson (dwJ) dwarf mice, mutations in the gene encoding Pit-1, a tissue-specific POU-domain transcription factor, lead to the absence of somatotroph, lactotroph and thyrotroph cells. Pre-somatotroph proliferation is stimulated by increased intracellular levels of cyclic AMP, normally induced by growth hormone releasing factor (GRF; refs 7-17). Here we report the cloning of mouse and rat complementary DNAs encoding a new member of the seven-transmembrane-helix, G-protein-coupled receptor family restricted to the pituitary gland, which mediates increases in intracellular cAMP and cAMP-dependent gene transcription in response to GRF. The receptor is expressed in a spatial and temporal pattern corresponding precisely to growth hormone gene expression, and neither is expressed in dw/dw mice. The pituitary hypoplasia in these mice thus appears to be due, at least in part, to the absence of GRF receptor, which is in turn due to the absence of functional Pit-1.

Amino Acid Sequence↗

PubMed2003

Epithelial colonies cultured from human explanted liver in subacute hepatic failure exhibit hepatocyte, biliary epithelial, and stem cell phenotypic markers.

The liver in subacute hepatic failure may become enriched for hepatic progenitor cells. Liver tissue from such a patient was collagenase digested and, from the nonparenchymal cell fraction, epithelioid colonies were developed. Albumin and alpha-1-antitrypsin (AAT) were secreted for greater than 120 days from these colonies. Reverse transcription-polymerase chain reaction showed expression of markers of both hepatocyte and biliary epithelial phenotypes (cytokeratins 7, 18, and 19, albumin and AAT, hepatocyte growth factor receptor, transforming growth factor beta receptor type II, gamma-glutamyl transpeptidase, biliary glycoprotein). The cell cycle regulator p21 was also expressed. The POU domain transcription factor octamer-binding protein 4 was present in these cells, but not in RNA or cDNA prepared from adult human liver. These markers were maintained even after 165 days culture. Proliferating epithelial-like cells with combined hepatocyte- and biliary-epithelial-specific functional markers and a stem cell marker can be isolated from the nonparenchymal fraction of liver cells in subacute hepatic failure.

Bile Ducts, Intrahepatic↗

PubMed1998

Lymphoid-specific transcription mediated by the conserved octamer site: who is doing what?

The conserved octamer site found in the promoters of Immunoglobulin (Ig) genes has been identified early on as a key element for B cell-specific Ig promoter activity and has also been associated with expression of other B cell-specific genes. Several transcription factors--ubiquitous or cell-restricted--interact specifically with the octamer motif in B cells: Oct-1 and Oct-2 are POU domain transcription factors that bind directly to the octamer site and thereby can recruit the coactivator OBF-1 to the promoters of various genes. Yet, in spite of intense work, the precise role played by each of these factors for transcription activation through the octamer motif is unclear. In particular, genetic inactivation in mice of the lymphoid cell-specific transcription factor Oct-2 or of the B cell-specific coactivator OBF-1 led to surprising findings that are being discussed.

Animals↗

PubMed2001

Axbrn-1: a maternal transcript encodes a POU transcription factor that is later expressed in the developing central nervous system of axolotl embryos.

Axbrn-1 encodes a class III POU protein with a POU-specific domain and a POU homeodomain that is most similar to RHS2 from rat. In embryos Axbrn-1 transcripts are maternally inherited and persist through cleavage. New transcripts accumulate beginning at the mid-blastula transition. In gastrulating embryos Axbrn-1 RNA is in the dorsal marginal zone and by neurula it is in the neural folds and neural plate. Later, it is specific to the developing brain and anterior spinal cord. Transcriptional activation at the mid-blastula transition indicates that Axbrn-1 is among the earliest genes to be expressed in axolotl embryos.

Ambystoma mexicanum↗

PubMed2001

New functions for DNA binding domains.

How the same transcription factor can be both an activator and a repressor of transcription is a biological mystery. Rao describes work that shows that the structure of the transcription factor may actually change depending on the DNA sequence bound by the factor. This change in structure may influence the binding of activators or repressors of transcription, thus allowing a single transcription factor to have two different activities.

Animals↗

PubMed2005

Use of altered-specificity binding Oct-4 suggests an absence of pluripotent cell-specific cofactor usage.

Oct-4 is a POU domain transcription factor that is critical for maintaining pluripotency and for stem cell renewal. Previous studies suggest that transcription regulation by Oct-4 at particular enhancers requires the input of a postulated E1A-like cofactor that is specific to pluripotent cells. However, such studies have been limited to the use of enhancer elements that bind other POU-protein family members in addition to Oct-4, thus preventing a 'clean' assessment of any Oct-4:cofactor relationships. Other attempts to study Oct-4 functionality in a more 'stand-alone' situation target Oct-4 transactivation domains to DNA using heterologous binding domains, a methodology which is known to generate artificial data. To circumvent these issues, an altered-specificity binding Oct-4 (Oct-4RR) and accompanying binding site, which binds Oct-4RR only, were generated. This strategy has previously been shown to maintain Oct-1:cofactor interactions that are highly binding-site and protein/binding conformation specific. This system therefore allows a stand-alone study of Oct-4 function in pluripotent versus differentiated cells, without interference from endogenous POU factors and with minimal deviation from bound wild-type protein characteristics. Subsequently, it was demonstrated that Oct-4RR and the highly transactive regions of its N-terminus determined here, and its C-terminus, have the same transactivation profile in pluripotent and differentiated cells, thus providing strong evidence against the existence of such a pluripotent cell-specific Oct-4 cofactor.

Amino Acid Substitution↗

PubMed1999

The Oct-1 POU domain directs developmentally regulated nuclear translocation in Xenopus embryos.

Early embryonic development in Xenopus is characterized by transcriptional repression which is relieved at the mid-blastula stage. Here we show that most of the maternally inherited POU domain transcription factor Oct-1 is retained in the cytoplasm during early development, and that it gradually translocates to the nucleus around the mid-blastula transition. Overexpressed epitope-tagged Oct-1 exhibits highly similar localization properties compared to endogenous protein. The amino acid sequence that directs this developmentally regulated nuclear translocation resides in the POU domain. Our findings may suggest that cytoplasmic retention of Oct-1 facilitates or contributes to the repression of Oct-1 target genes before the mid-blastula transition.

Animals↗

PubMed1997

[Homeoproteins and pituitary adenoma].

Several transactivating factors specifically involved in the differentiation and proliferation of anterior pituitary cell types have been recently identified. Among them Pit-1 a member of the POU-domain transcription factors family is specific of anterior pituitary cells, and was initially identified and cloned as a transactivator of the GH and PRL genes and as a regulator of the TSH beta gene. Pit-1 play a key role during embryogenesis in the differentiation and proliferation of somatotrophs, lactotrophs and thyreotrophs. The importance of Pit-1 as a regulator in the anterior pituitary development has been further demonstrated by naturally occurring mutations or delections in dwarf mouse strains. In the Snell and Jackson dwarf mice, the levels of Pit-1 gene expression are low or undetectable, GH, PRL and TSH beta gene expression are absent and lactotrophs, somatotrophs, and threotrophs fail to proliferate. Furthermore Pit-1 carries out similar functions in humans. This is supported by the fact that children with mutations of the Pit-1 gene present with a congenital combined GH, PRL and TSH deficiency analogous to the phenotype of the Snell and Jackson dwarf mice. In children who were born to healthy consanguinous parents and present such combined deficiencies we recently reported a Pit-1 mutation causing a transition from a Phe to a Cys in a region of the protein known to be involved in DNA binding. Pit-1 transcripts identical in size and sequence to those observed in normal pituitary were described in human GH, PRL and TSH secreting pituitary adenomas. The Pit-1 beta isoform, raised through alternative splicing of exon 2 of the Pit-1 gene, is a more potent inducer of GH transcription than the major Pit-1 form. However no difference in the level of expression of the different Pit-1 isoforms was observed between tumors identified as pure GH or PRL producing tumors. The results support the existence of other transcription factors interacting with Pit-1 to coordinately regulate the activity of the GH and PRL promotors in a cell specific manner. In contrast, variable Pit-1 expression was observed in prolactinomas, according to their sensitivity to bromocriptine treatment. A highly significant correlation was indeed evidenced between the D2 receptors mRNA and the Pit-1 mRNA levels. These results raise the possibility that Pit-1 may either directly or indirectly affect the transcription of the D2 dopaminergic receptor gene. In fact, receptors for other hypothalamic neurohormones such a GHRH and somatostatin are known to be potential Pit-1 target genes. Such mechanisms could be implicated in the differentiation and proliferation of lactotrophs and somatotrophs.

Adenoma↗

PubMed1997

Cysteine 50 of the POU H domain determines the range of targets recognized by POU proteins.

The best target of POU proteins (Oct-1, Oct-2) is an octamer sequence ATGCAAAT. POU proteins also recognize, with weaker affinity, the TAAT-like targets of another group of regulatory factors, the homeoproteins. Up to now, it has not been known why Cys50 of the POUHdomain is absolutely conserved in contrast to that in homeoproteins. To assess the importance of Cys50 in determining the binding specificity of POU proteins, all possible amino acids were substituted for Cys at position 50, and the resulting mutants were tested with probes containing octamer (ATGCAAATNN) or homeospecific binding sites. Only the wild-type POU was shown to adequately discriminate between the octamer and homeospecific sites, and the protein affinity was only slightly affected by the nucleotide sequence flanking the octamer at the 3'-end. Any amino acid substitution at position 50 resulted in the mutant protein binding efficiently both to the octamer and the TAAT-like sequences. Moreover, in this case the 3'-flanking sequences influenced the binding to a much greater extent.

Binding Sites↗

PubMed2005

Redundant and synergistic effect of Cdx-2 and Brn-4 on regulating proglucagon gene expression.

Cdx-2 and Brn-4 are recognized as transcriptional activators for the proglucagon gene. These two homeodomain (HD) proteins are able to interact with the correspondent motifs on the G1 enhancer element of proglucagon promoter, separated by only 8 bp. We have examined Brn-4 expression in proglucagon-producing cells, isolated hamster Brn-4 cDNA, and localized its activation domain. Ectopic expression of either Cdx-2 or Brn-4 in the pancreatic B cell line In111 provoked it to express proglucagon mRNA, whereas ectopically expressing both of them further stimulated proglucagon mRNA expression in this cell line. Furthermore, Brn-4 was found to synergize with Cdx-2 in activating proglucagon promoter, and the Brn-4 activation domain was not required for this synergistic activation. When the binding site for either Cdx-2 or Brn-4 was mutated, the synergistic activation by these two HD proteins was significantly attenuated, but not abolished. We propose that both cooperative DNA binding and mutual recruitment between Cdx-2 and Brn-4 are involved in this synergistic activation and have detected physical interaction between Cdx-2 and Brn-4 by glutathione-S-transferase-fusion protein pull-down assay. Our observations suggest that Cdx-2 and Brn-4, two HD proteins that belong to two different families, exert a synergistic and redundant effect on proglucagon gene expression.

Animals↗

PubMed2002

Structural characterization of the PIT-1/ETS-1 interaction: PIT-1 phosphorylation regulates PIT-1/ETS-1 binding.

The POU-domain transcription factor Pit-1 and Ets-1, a member of the ETS family of transcription factors, can associate in solution and synergistically activate the prolactin promoter by binding to a composite response element in the prolactin promoter. We mapped the minimal region of Ets-1 required for the interaction with the Pit-1 POU-homeodomain. Here, we describe a detailed NMR study of the interaction between the POU-homeodomain of Pit-1 and the minimal interacting region of Ets-1. By using heteronuclear single quantum coherence titration experiments, we were able to map exact residues on the POU-homeodomain that are involved in the interaction with this minimal Ets-1 interaction domain. By using our NMR data, we generated point mutants in the POU-homeodomain and tested their effect on the interaction with Ets-1. Our results show that phosphorylation of Pit-1 can regulate the interaction with Ets-1.

Animals↗

PubMed2001

Gene expression profile in streptozotocin-induced diabetic mice kidneys undergoing glomerulosclerosis.

BACKGROUND: To elucidate the molecular mechanism of diabetic nephropathy, a high-density DNA filter array was employed to survey the gene expression profile of streptozotocin-induced diabetic CD-1 (ICR) mouse kidneys. METHODS: Ten-week-old CD-1 male mice were divided into four groups: (1) control, (2) unilaterally nephrectomized (UX) mice, (3) streptozotocin (STZ)-induced diabetic (STZ) mice, and (4) STZ mice with unilateral renal ablation (STZ-UX). Pathological changes were examined at 24 weeks after the induction. The gene expression profile was compared between the control and STZ mice by a Gene Discovery Array (GDA). RESULTS: The glomeruli in UX mouse kidney showed prominent glomerular hypertrophy, while the accumulation of mesangial matrix was minimal. Both STZ and STZ + UX mice had significant glomerular hypertrophy and glomerulosclerosis, and the lesions were not enhanced by renal ablation. By comparison between control and STZ mice, 16 clones that increased in expression with the induction of diabetes and 65 clones that decreased in diabetic kidneys were identified. The 37 known genes were related to glucose and lipid metabolism, ion transport, transcription factors, signaling molecules, and extracellular matrix-related molecules. The genes known to be involved in cell differentiation and organogenesis in various tissues (that is, Unc-18 homolog, POU domain transcription factor 2, lunatic fringe gene homolog, fibrous sheath component 1, Sox-17, fibulin 2, and MRJ) were found to be differentially expressed in the early phase of diabetic kidneys. CONCLUSIONS: Hyperglycemia is a major determinant of glomerulosclerosis in STZ-induced diabetic CD-1 mice, and the altered gene expression in the early phase of diabetic kidney may be critical for the development of diabetic nephropathy.

Animals↗

PubMed1999

Identification of dividing, determined sensory neuron precursors in the mammalian neural crest.

Sensory and autonomic neurons of the vertebrate peripheral nervous system are derived from the neural crest. Here we use the expression of lineage-specific transcription factors as a means to identify neuronal subtypes that develop in rat neural crest cultures grown in a defined medium. Sensory neurons, identified by expression of the POU-domain transcription factor Brn-3.0, develop from dividing precursors that differentiate within 2 days following emigration from the neural tube. Most of these precursors generate sensory neurons even when challenged with BMP2, a factor that induces autonomic neurogenesis in many other cells in the explants. Moreover, BMP2 fails to prevent expression of the sensory-specific basic helix-loop-helix (bHLH) transcription factors neurogenin1, neurogenin2 and neuroD, although it induces expression of the autonomic-specific bHLH factor MASH1 and the paired homeodomain factor Phox2a in other cells. These data suggest that there are mitotically active precursors in the mammalian neural crest that can generate sensory neurons even in the presence of a strong autonomic-inducing cue. Further characterization of the neurons generated from such precursors indicates that, under these culture conditions, they exhibit a proprioceptive and/or mechanosensory, but not nociceptive, phenotype. Such precursors may therefore correspond to a lineally (Frank, E. and Sanes, J. (1991) Development 111, 895-908) and genetically (Ma, Q., Fode, C., Guillemot, F. and Anderson, D. J. (1999) Genes Dev. 13, in press) distinct subset of early-differentiating precursors of large-diameter sensory neurons identified in vivo.

Animals↗

PubMed1994

A survey of genes expressed in undifferentiated mouse embryonal carcinoma F9 cells: characterization of low-abundance mRNAs.

As a first step to catalogue mRNAs present in mouse embryonal carcinoma F9 cells, 879 clones corresponding to low-abundance mRNAs were selected from among 2,896 randomly picked up clones of undifferentiated F9 cDNA libraries, using DNA probes complementary to poly(A)+RNAs prepared from undifferentiated F9 cells and to ones prepared from mouse fibroblast L cells. Five-hundred and eighty-two of the 879 clones were partially sequenced, and the subsequent homology search revealed that 201 corresponded to 180 known genes or known DNA sequences, which include not only housekeeping genes but also various tissue-specific genes. Interestingly, at least 24 of the 180 genes are development-related genes in mammals. Among these 24, those for midkine (growth and/or differentiation factor) and interferon-beta are reportedly up-regulated, and those for ECA39 (target for c-Myc regulation), REX-1 (zinc finger protein), and OCT-3 (POU-domain transcription factor) are down-regulated during the development of mouse embryonal carcinoma cells. Thirty-seven of the 582 clones matched the 36 previously reported unidentified ESTs (expressed sequence tags) and the remaining 344 corresponded to 329 novel ESTs. Therefore, partial sequencing of F9 cDNA clones corresponding to low-abundance mRNAs in F9 cells not only provides valuable information concerning development-related genes in mammals, but also many novel ESTs useful for studying mammalian genomes.

Animals↗

PubMed1993

Zebrafish pou[c]: a divergent POU family gene ubiquitously expressed during embryogenesis.

We report the isolation and characterization of cDNA for a novel zebrafish (Brachyodanio rerio) POU domain gene, pou[c], which is ubiquitously expressed during embryonic development. This gene encodes a 610 amino acids long protein with a 149 amino acid POU domain ending only 8 residues before the C terminus. The 453 amino acids long region N-terminal to the POU domain contains several features typical of transcriptional activation domains such as an acidic region with a putative amphipathic alpha-helix, a glutamine-rich region, and short threonine- and/or serine-rich regions. Comparison of the POU domain of pou[c] to other known POU sequences clearly show that pou[c] has the most divergent POU domain sequence reported to date. Thus, we suggest that pou[c] should be placed as the presently sole member of a new, sixth class of POU proteins. DNA-binding studies revealed that pou[c] is not an octamer-binding transcription factor like the Oct proteins described from mammals, chicken and Xenopus. Rather, pou[c] binds with high affinity to the TAATGARAT motif found in the promoters of the herpes simplex virus immediate early genes and to degenerate octamer-TAATGA motifs. Circular permutation analyses also show that pou[c] induces DNA bending upon sequence-specific binding.

Amino Acid Sequence↗