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PubMed1994

NMDA receptor activation in differentiating cerebellar cell cultures regulates the expression of a new POU gene, Cns-1.

POU/homeobox genes encode transcription regulatory proteins that are important in defining cellular phenotypes. Expression of these genes may be critical for to the regulation of CNS cellular differentiation. We have identified a cDNA corresponding to a new member of the POU/homeobox gene family. Expression of RNA encoded by this new gene occurs predominantly in the CNS. Thus, this new gene was designated Cns-1. Cns-1 transcripts are expressed in differentiating cells cultured from the early postnatal cerebellum. Treatment of these cultured cells with NMDA results in an increase in the level of Cns-1 RNA. This increase is blocked by simultaneous treatment with the specific NMDA receptor antagonist amino-5-phosphonovaleric acid. Continued activation of the NMDA receptor allows maintenance of this new steady state level of Cns-1 mRNA for at least 5 d in these cultured cells. A transcription runoff assay suggests that this increase in the level of RNA is due, at least in part, to an increase in transcription from the Cns-1 gene. The NMDA-induced increase in Cns-1 mRNA was reduced by pretreatment with calcium chelators EGTA or 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) tetrakis(acetoxymethyl). These studies suggest that specific activation of the NMDA receptor in cultures of differentiating cerebellar cells increases Cns-1 gene expression and that calcium entry through the NMDA channel may be required for this response. This change in Cns-1 expression may modify phenotypic characteristics of these cultured cells.

Amino Acid Sequence↗
PubMed1993

A novel class of murine POU gene predominantly expressed in central nervous system.

A mouse gene (referred to as Emb) encoding a novel class of POU domain is described. The Emb POU domain shares only 40-50% homology to that of any other POU proteins. Nonetheless, the Emb POU domain can bind to the octamer sequence like other POU domains. Emb is a single-copy gene, located on the distal region of mouse chromosome 15. It is expressed in embryo throughout post-implantation stages, where the most prominent expression is seen in developing central nervous system. In the adult, it is highly expressed in brain, whereas weaker expression can be detected in other organs such as testis, skeletal muscle, and kidney. The expression in adult brain is most evident in neurons of hypocampus formation. Two types of Emb mRNA are expressed in brain; one type encodes a protein of 301 amino acids residues, whereas the other codes for a protein with two extra amino acids residues added at the amino-terminal end of POU domain. These two mRNA species are generated by alternative splicing by utilizing an unusual splice acceptor site: CCTCCCTCTG/. Emb mRNA expressed in testis, on the other hand, encodes a smaller protein lacking most of the amino-terminal region.

Amino Acid Sequence↗
PubMed1998

Promyelinating Schwann cells express Tst-1/SCIP/Oct-6.

Tst-1/SCIP/Oct-6, a POU domain transcription factor, is transiently expressed by developing Schwann cells and is required for their normal development into a myelinating phenotype. In tst-1/scip/oct-6-null sciatic nerves, Schwann cells are transiently arrested at the "promyelinating" stage, when they have a one-to-one relationship with an axon but before they have elaborated a myelin sheath. To determine when Schwann cells express Tst-1/SCIP/Oct-6, we examined beta-galactosidase (beta-gal) expression in heterozygous tst-1/scip/oct-6 mice, in which one copy of the tst-1/scip/oct-6 gene has been replaced with the LacZ gene. beta-Gal expression from the LacZ gene seems to parallel Tst-1/SCIP/Oct-6 expression from the endogenous tst-1/scip/oct-6 gene in developing and regenerating sciatic nerves. Furthermore, electron microscopic examination of 5bromo-4-chloro-3-indolyl-beta-D-galactopyranoside- (X-gal) and halogenated indolyl-beta-D-galactoside- (Bluo-gal) stained nerves showed that promyelinating Schwann cells express the highest levels of beta-gal, both in developing and in regenerating nerves. Thus, the expression of beta-gal, a surrogate marker of Tst-1/SCIP/Oct-6, peaks at the same stage of Schwann cell development at which development is arrested in tst-1/scip/oct-6-null mice, indicating that Tst-1/SCIP/Oct-6 has a critical role in promyelinating Schwann cells.

Age Factors↗
PubMed2005

Brn3a-expressing retinal ganglion cells project specifically to thalamocortical and collicular visual pathways.

Retinal ganglion cells (RGCs) innervate several specific CNS targets serving cortical and subcortical visual pathways and the entrainment of circadian rhythms. Recent studies have shown that retinal ganglion cells express specific combinations of POU- and LIM-domain transcription factors, but how these factors relate to the subsequent development of the retinofugal pathways and the functional identity of RGCs is mostly unknown. Here, we use targeted expression of an genetic axonal tracer, tau/beta-galactosidase, to examine target innervation by retinal ganglion cells expressing the POU-domain factor Brn3a. Brn3a is expressed in RGCs innervating the principal retinothalamic/retinocollicular pathway mediating cortical vision but is not expressed in RGCs of the accessory optic, pretectal, and hypothalamic pathways serving subcortical visuomotor and circadian functions. In the thalamus, Brn3a ganglion cell fibers are primarily restricted to the outer shell of the dorsal lateral geniculate, providing new evidence for the regionalization of this nucleus in rodents. Brn3a RGC axons have a relative preference for the contralateral hemisphere, but known mediators of the laterality of RGC axons are not repatterned in the absence of Brn3a. Brn3a is coexpressed extensively with the closely related factor Brn3b in the embryonic retina, and the effects of the loss of Brn3a in retinal development are not severe, suggesting partial redundancy of function in this gene class.

Animals↗
PubMed1994

Homeodomain determinants of major groove recognition.

The homeodomain is a highly conserved structural module that binds DNA and participates in protein-protein interactions. Most homeodomains contain residues at positions 47 and 51 which mediate recognition of a TAAT core binding sequence in the major groove. The constraints imposed on the identity of these residues by homeodomain structure and DNA docking have been examined in the context of the POU domain of the Oct-1 transcription factor. A bacterial library, in which POU homeodomain residues 47 and 51 have been randomized, was probed on nitrocellulose filters for the binding of DNA fragments containing the consensus octamer sequence. The residues which provide for the highest affinity interaction with the octamer consensus sequence, and the greatest specificity, are the highly conserved wild-type residues valine 47 and asparagine 51. Interestingly, a class of variants containing arginine at position 51 was also detected in the screen and found to have moderate affinity for the consensus sequence but reduced specificity compared to the wild-type protein. A single variant containing arginine at both positions 47 and 51 was detected when the library was probed with fragments containing nucleotide substitutions at positions expected to be contacted by residues 47 and 51. This variant was used to alter the DNA-binding specificity of a transcriptional regulatory complex which depends upon Oct-1 for DNA recognition. These findings suggest that homeodomain structure and DNA docking constrain in the versatility of the domain in that only a limited set of amino acid determinants can endow the domain with specific, high-affinity DNA binding.

Base Sequence↗
PubMed1997

The carboxy-terminal transactivation domain of Oct-4 acquires cell specificity through the POU domain.

The POU transcription factor Oct-4 is expressed in totipotent and pluripotent cells of the early mouse embryo and the germ cell lineage. Transactivation capacities of regions flanking the DNA binding domain of Oct-4 were analyzed in undifferentiated and differentiated cell lines. The amino- and carboxy-terminal regions (N domain and C domain) fused to the Gal4 DNA binding domain both functioned as transactivation domains in all cell lines tested. However, the C domain failed to activate transcription in some cell lines in the context of the native protein. The underlying regulatory mechanism appears to involve the POU domain of Oct-4 and can discriminate between different POU domains, since constructs in which the C domain was instead fused to the POU domain of Pit-1 were again equally active in all cell lines. These results indicate that the C domain is subject to cell-type-specific regulation mediated by the Oct-4 POU domain. Phosphopeptide analysis revealed that the cell-type-specific difference of C-domain activity correlates with a difference in Oct-4 phosphorylation status. Since Oct-4 is expressed in a variety of distinct cell types during murine embryogenesis, these results suggest an additional regulatory mechanism for determining Oct-4 function in rapidly changing cell types during development.

3T3 Cells↗
PubMed1992

Mapping the transactivation domain of the Oct-6 POU transcription factor.

The POU transcription factor Oct-6 is expressed in embryonic stem cells, glial progenitor cells and in a restricted set of neurons in the CNS. The protein has been shown to act as a transactivator as well as a repressor. Here we show that the Oct-6 protein activates transcription from three different promoters in HeLa cells. The ability to activate a minimal tk promoter via a multimerized IgH enhancer octamer motif relies on a domain within the aminoterminal third of the protein. Parts of this domain can be deleted without abolishing transactivation, suggesting that there is functional redundancy within this region. The transactivation domain of the Oct-6 protein is different from other described activation domains in that it is highly glycine and alanine rich.

Animals↗
PubMed2004

Regulation of growth hormone expression by thyrotropin-releasing hormone through the pituitary-specific transcription factor Pit-1 in chicken pituitary.

Pit-1 is a pituitary-specific POU-domain DNA binding factor, which binds to and trans-activates promoters of growth hormone- (GH), prolactin- (PRL) and thyroid stimulating hormone beta- (TSHbeta) encoding genes. Pit-1 has been identified in several mammalian and avian species. Thyrotropin-releasing hormone (TRH) is located in the hypothalamus and it stimulates TSH, GH and PRL release from the pituitary gland. In the present study, we successfully developed a competitive RT-PCR for the detection of Pit-1 expression in the chicken pituitary, that was sensitive enough to detect picogram levels of Pit-1 mRNA. Applying this method, the effect of TRH injections on Pit-1 mRNA expression was determined in the pituitary of chick embryos and growing chicks. In both 18-day-old embryos and 10-day-old male chicks the Pit-1 mRNA expression was significantly increased following TRH injection, thereby indicating that the stimulatory effects of TRH on several pituitary hormones is mediated via its effect on Pit-1 expression. Therefore, a semi-quantitative RT-PCR method was used to detect possible changes in GH levels. TRH affected the GH mRNA levels at both developmental stages. These results, combined with the data on Pit-1 mRNA expression, indicate that Pit-1 has a role in mediating the stimulatory effects of TRH on pituitary hormones like GH.

Animals↗
PubMed2003

Homologous recombination in human embryonic stem cells.

Homologous recombination applied to mouse embryonic stem (ES) cells has revolutionized the study of gene function in mammals. Although most often used to generate knockout mice, homologous recombination has also been applied in mouse ES cells allowed to differentiate in vitro. Homologous recombination is an essential technique if human ES cells are to fulfill their promise as a basic research tool. It also has important implications for ES cell-based transplantation and gene therapies. Significant differences between mouse and human ES cells have hampered the development of homologous recombination in human ES cells. High, stable transfection efficiencies in human ES cells have been difficult to achieve, and, in particular, electroporation protocols established for mouse ES cells work poorly in human ES cells. Also, in contrast to their murine counterparts, human ES cells cannot be cloned efficiently from single cells, making it difficult to screen for rare recombination events. Here we report an electroporation approach, based on the physical characteristics of human ES cells, that we used to successfully target HPRT1, the gene encoding hypoxanthine phosphoribosyltransferase-1 (HPRT1), and POU5F1, the gene encoding octamer-binding transcription factor 4 (Oct4; also known as POU domain, class 5, transcription factor 1 (POU5F1)).

DNA-Binding Proteins↗
PubMed1997

[The pituitary specific transcription factor Pit-1/GHF-1 and PIT1 abnormality].

Pit-1/GHF-1 is a pituitary specific POU-domain DNA binding factor, which transactivates the growth hormone (GH), prolactin (PRL), thyrotropin beta subunit (TSH beta) genes, and PIT1 gene itself. It is indispensable for the differentiation and the proliferation of the cells producing GH, and PRL. Loss of the PIT1 gene function (PIT1 abnormality) results in combined deficiency of GH, PRL, and TSH. PIT1 abnormality serves as a model of transcription factor abnormalities.

Animals↗
PubMed1994

Site-specific conformational alteration of the Oct-1 POU domain-DNA complex as the basis for differential recognition by Vmw65 (VP16).

We show that the presence of a regulatory cis-acting element that flanks the core octamer site and dictates selectivity in the response to Vmw65 (VP16), while dispensable for POU binding per se, induces a conformational alteration in the nature of the POU domain in the DNA complex. A single substitution in the flanking signal distorts the POU complex and without affecting overall POU binding prevents Vmw65 interaction. Alternatively, substitution of a residue in the homeodomain predicted to contact the GARAT region prevents its recognition even on a wild-type motif, causing a reversion to the DNA binding pattern seen on a cellular motif and at the same time inefficient recognition by Vmw65. The results indicate that Vmw65 recognizes a particular POU domain conformation induced by the presence of the flanking GARAT region.

Base Sequence↗
PubMed1993

Murine chromosomal location of four class III POU transcription factors.

A family of mouse genes encoding class III POU transcription factors consists of four members: Oct-6, Brn-2, Brn-1, and Brn-4. In accordance with mouse nomenclature, these loci have been designated Otf-6, Otf-7, Otf-8, and Otf-9, respectively. While the four genes share a highly conserved class III POU domain, the remaining regions are considerably diverged from each other. The POU domains of these transcription factors recognize the octamer-motif sequence and possess a similar DNA-binding specificity. Chromosomal mapping has demonstrated that the four genes are unlinked: Otf-6 is located on the distal region of chromosome 4, Otf-7 on the proximal region of chromosome 4, Otf-8 on chromosome 1, and Otf-9 on the X chromosome.

Animals↗
PubMed2000

Complementary DNA cloning and ontogenic expression of pituitary-specific transcription factor of chickens (Gallus domesticus) from the pituitary gland.

Pit-1 is a pituitary-specific POU-domain DNA binding factor, which binds to and transactivates promoters of growth hormone (GH)-, prolactin (PRL)-, and thyroid-stimulating hormone-beta (TSHbeta)-encoding genes. Pit-1 has been identified in several mammalian species. In birds, it has been identified only in the turkey and chicken pituitary. Several (gg) Pit-1 cDNA sequences have been identified in the anterior pituitary of the chicken (Gallus domesticus). As in turkey, three different transcripts (ggPit-1*, ggPit-1beta*, and ggPit-1W*) of the Pit-1 gene were identified. This suggests that the chicken pituitary expresses more variants than reported earlier. Previous studies have concentrated on expressions during posthatch life of the turkey and chicken. The present study has determined the ontogeny of Pit-1 during the embryonic life of the chicken (day 1-day 21 of incubation). The mRNA for Pit-1 was first detected in the pituitary on day 5 of embryonic life. The expression of the mRNA was maintained until hatch. The presence of Pit-1 at this stage of embryonic development suggests that Pit-1 may be physiologically important during embryonic development of birds, as it precedes the gene expression and secretion of GH, PRL, and TSHbeta. A similar sequence for the expression of Pit-1 relative to GH and PRL during embryonic/fetal development has been reported for rodents.

Amino Acid Sequence↗
PubMed1997

The Oct-1 POU homeodomain stabilizes the adenovirus preinitiation complex via a direct interaction with the priming protein and is displaced when the replication fork passes.

Initiation of adenovirus DNA replication is strongly enhanced by two cellular transcription factors, NFI and Oct-1, which bind to the auxiliary origin and tether the viral precursor terminal protein-DNA polymerase (pTP.pol) complex to the core origin. NFI acts through a direct contact with the DNA polymerase, but the mode of action of Oct 1 is unknown. Employing glutathione S-transferase-POU pull-down assays and protein affinity chromatography, we have established that the POU domain contacts pTP rather than pol. The POU homeodomain is responsible for this interaction. The protein-protein contacts lead to increased binding of pTP-pol to the core origin, which is caused by a reduced off-rate. The enhanced formation of a pTP.pol.POU complex on the origin correlates with stimulation of replication. Using an immobilized replication system, we have studied the kinetics of dissociation of the Oct-1 POU domain during replication. In contrast to NFI, which dissociates very early in initiation, Oct-1 dissociates only when the binding site is rendered single-stranded upon translocation of the replication fork. Our data indicate that NFI and Oct-1 enhance initiation synergistically by touching different targets in the preinitiation complex and dissociate independently after initiation.

Adenoviridae↗
PubMed1998

POU domain genes are differentially expressed in the early stages after lineage commitment of the PNS-derived stem cell line, RT4-AC.

RT4 is a family of cell lines derived from a rat peripheral neurotumor and consists of a multipotential stem cell which spontaneously gives rise to a glial derivative and two neuronal derivatives. To begin to understand the role(s) of transcription factors in neural differentiation, we examined the expression of ten transcription factor genes (MASH1, REST/NRSF, Oct-1, Oct-2, Tst-1/SCIP, Brn-1, Brn-2, Brn-3.0, Brn-4, Brn-5) in the RT4 cell lines. We report here that all of the RT4 cells express REST/NRSF, Oct-1 and Brn-5, but do not express MASH1, Brn-3.0 or Brn-4. Furthermore, Brn-2 and Tst-1/SCIP expression was restricted to the RT4 stem cell line and glial derivative, while Oct-2 was expressed predominantly by the RT4 stem cell line and neuronal derivatives. We propose that the lack of expression of MASH1 (which is expressed relatively early in autonomic neuron differentiation) and Brn-3.0 (which is expressed early in sensory neuron differentiation), in combination with the presence of REST/NRSF (a repressor of neuronal gene expression), in all of the RT4 cell lines, establishes the RT4 system as a unique model for examining very early events in neuronal versus glial cell fate determination.

3T3 Cells↗
PubMed1994

[Pituitary specific transcription factor Pit-1/GHF-1 and combined pituitary hormone deficiency].

Pit-1/GHF-1 is a pituitary-specific POU-domain DNA binding factor, which binds to, and trans-activates the promoters of both growth hormone (GH) and prolactin (PRL) genes. It is well conserved among vertebrates and is indispensable for both differentiation and proliferation of the somatotrophs, lactotrophs and thyrotrophs. PIT1 abnormality is defined as a genetic abnormality in the PIT1 gene, and results in various types of combined deficiencies of thyrotropin (TSH), GH, and PRL. PIT1 abnormality was first recognized as an excellent model for 'transcription factor disease'. Recently, we found a novel case whose cannot be explained by the PIT1 gene mutation alone. Such case will give us precious clue to identify modifier factors of Pit-1/GHF-1.

Animals↗