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Results for “POU Domain Factors”

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PubMed2005

Alcohol alters insulin-like growth factor-1 activated oct 2 POU domain gene expression in the immature female hypothalamus.

OBJECTIVE: The Oct 2 POU homeodomain gene has been shown to increase during late juvenile development; the upstream control of Oct 2 is not known, however. The insulin-like growth factor-1 (IGF-1) is known to act centrally to stimulate luteinizing hormone (LH)-releasing hormone (LHRH) release and advance female puberty. We therefore sought to determine if this peptide induces transcription of Oct 2 genes as an early pubertal event. Furthermore, as alcohol (ALC) blocks IGF-1-induced LHRH and LH release acutely, we aimed to determine if it could affect the ability of IGF-1 to stimulate Oct 2 gene expression. METHOD: Female rats, 25 days old, were administered saline or IGF-1 (rat IGF-1 20 ng/3 microI) in the third ventricle at 0900 hours and killed 2, 4 and 6 hours later for assessment of Oct 2 gene expression in the preoptic area (POA) and the medial basal hypothalamus (MBH). In another experiment, we determined whether ALC (3 g/kg) could block IGF-1-induced Oct 2 gene expression. RESULTS: In the POA, IGF-1 did not affect the expression of Oct 2a, but it increased the Oct 2c mRNA levels at 2 hours. In the MBH, both transcripts were elevated 4 hours after IGF-1 stimulation. ALC did not alter basal expression of either of the Oct 2 gene isoforms. In both regions, however, ALC blocked IGF-1-induced gene expression. CONCLUSIONS: IGF-1 induced Oct 2 genes prior to the normal increase during the late juvenile period, indicating this IGF- 1 induction may be an early event in the activation of the LHRH secretory pathway. ALC blocks this action, suggesting the Oct 2 POU gene is a likely target by which ALC can interfere with glial-neuronal interactions and interrupt LHRH secretion during prepubertal development.

Actins↗

PubMed2003

Human melanoblasts in culture: expression of BRN2 and synergistic regulation by fibroblast growth factor-2, stem cell factor, and endothelin-3.

The BRN2 transcription factor (POU3F2, N-Oct-3) has been implicated in development of the melanocytic lineage and in melanoma. Using a low calcium medium supplemented with stem cell factor, fibroblast growth factor-2, endothelin-3 and cholera toxin, we have established and partially characterised human melanocyte precursor cells, which are unpigmented, contain immature melanosomes and lack L-dihydroxyphenylalanine reactivity. Melanoblast cultures expressed high levels of BRN2 compared to melanocytes, which decreased to a level similar to that of melanocytes when cultured in medium that contained phorbol ester but lacked endothelin-3, stem cell factor and fibroblast growth factor-2. This decrease in BRN2 accompanied a positive L-dihydroxyphenylalanine reaction and induction of melanosome maturation consistent with melanoblast differentiation seen during development. Culture of primary melanocytes in low calcium medium supplemented with stem cell factor, fibroblast growth factor-2 and endothelin-3 caused an increase in BRN2 protein levels with a concomitant change to a melanoblast-like morphology. Synergism between any two of these growth factors was required for BRN2 protein induction, whereas all three factors were required to alter melanocyte morphology and for maximal BRN2 protein expression. These finding implicate BRN2 as an early marker of melanoblasts that may contribute to the hierarchy of melanocytic gene control.

Antigens, Neoplasm↗

PubMed1993

Solution structure of the POU-specific DNA-binding domain of Oct-1.

The transcription factor Oct-1 belongs to a family containing a POU DNA-binding domain. This bipartite domain is composed of a POU-specific domain (POUs) and a POU-homeodomain (POUhd) connected by a flexible linker. The left half of the optimal POU binding site, the octamer ATGCAAAT, is recognized by POUs and the right half by POUhd. We have determined the solution structure of POUs by nuclear magnetic resonance. It consists of four alpha-helices connected by short loops. Helices I and IV are in a parallel coiled-coil arrangement. The folding topology appears to be similar to that of the bacteriophage lambda-repressor and 434 repressor. For the well defined parts of the protein (residues 1-71), the average root-mean square deviation for the backbone atoms is 0.9 A. Based on the observed selective exchange broadening in the (15N,1H)-HMQC (heteronuclear multiple quantum coherence) spectrum of the POUs-DNA complex we conclude that DNA-binding is mediated by helix III. We propose a model for the POU-DNA complex in which both recognition helices from the two subdomains have adjacent positions in the major groove.

Amino Acid Sequence↗

PubMed2005

The neuronal POU transcription factor Brn-2 interacts with Jab1, a gene involved in the onset of neurodegenerative diseases.

Brain-2 (Brn-2), a Class III POU transcription factor, plays an important role in the development of the neocortex and the establishment of neural cell lineage. Here we performed a yeast two-hybrid screening to identify the Brn-2 binding proteins. We obtained Jun-activation-domain-binding protein 1 (Jab1) as a new Brn-2 binding protein. Direct interaction between Brn-2 and Jab1 was confirmed by using a surface plasmon resonance biosensor. Considering the involvement of Jab1 in the onset of the neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, the interaction between Brn-2 and Jab1 may provide some insights into the understanding of neuronal development and neurodegenerative diseases.

Animals↗

PubMed2004

Identification of a POU factor involved in regulating the neuron-specific expression of the gene encoding diapause hormone and pheromone biosynthesis-activating neuropeptide in Bombyx mori.

Diapause hormone (DH) and PBAN (pheromone biosynthesis-activating neuropeptide) are two important insect neuropeptides regulating development and reproduction respectively. In the present study, we report two Bombyx mori transcription factors interacting specifically with the promoter of Bom-DH-PBAN (where Bom-DH stands for B. mori DH); we named them DHMBP-1 and -2 (DH-modulator-binding proteins 1 and 2). The developmental changes of DHMBP-1/-2 are closely correlated with that of Bom-DH-PBAN mRNA throughout the pupal stage. Competition assays indicate that DHMBP-1 from Chinese B. mori possesses binding characteristics similar to those of the POU-M1 protein from Japanese B. mori. POU-M1 cDNAs were cloned from various tissues of Chinese B. mori and were found to be distinct from the previously published POU-M1 in amino acid residues 108-136 because of insertion mutations. Owing to this difference in amino acid residues, we named this cDNA POU-M2. Even though POU-M2 differs from POU-M1 at the N-terminal, the POU domain and the binding properties of both POU-M1 and -M2 are the same. Functional analysis showed that overexpression of POU-M2 in the Bombyx cell line BmN activated the promoter of Bom-DH-PBAN, but failed to activate a promoter in which the POU-binding element was mutated. The transcriptional activity of POU-M2 is probably regulated by other factors binding to the upstream of the promoter sequence. We show that the POU-M2-binding site was able to activate the transcription of a heterologous promoter of the gene encoding B. mori larval serum protein. POU-M1 was found to exhibit the same transcriptional activities as POU-M2. Taken together, these results demonstrate that POU-M2 plays an important role in the transcriptional regulation of the Bom-DH-PBAN gene.

Amino Acid Sequence↗

PubMed1998

Bcl-2 transcription from the proximal P2 promoter is activated in neuronal cells by the Brn-3a POU family transcription factor.

The BCL-2 protein is able to protect neuronal and other cell types from apoptotic programmed cell death and plays a key role in regulating the rate of apoptosis during development of the nervous system. We have previously demonstrated that the Brn-3a POU domain transcription factor protects sensory neurons from apoptotic programmed cell death induced by nerve growth factor withdrawal. We report here that Bcl-2 transcription is predominantly initiated from the Bcl-2 P2 promoter in both the ND7 neuronal cell line and primary dorsal root ganglion neurons, in contrast to the predominant use of the Bcl-2 P1 promoter in other cell types. Moreover, Bcl-2 transcription initiated from the P2 region increases in ND7 cells stably overexpressing Brn-3a, resulting in enhanced BCL-2 protein levels. Similarly, the Bcl-2 P2 promoter is directly activated by Brn-3a in co-transfection assays in both ND7 cells and dorsal root ganglion neurons. Analysis of the Bcl-2 regulatory sequence revealed a binding site for Brn-3a that is required for maximal activation by Brn-3a both in transfected cells and during differentiation of ND7 cells. Together these data identify Brn-3a as the first transcription factor regulating Bcl-2 activity specifically in neuronal cells and indicate that the anti-apoptotic effect of Brn-3a is likely to be mediated, at least in part, via the up-regulation of Bcl-2 expression.

Base Sequence↗

PubMed1991

Variable effects of phosphorylation of Pit-1 dictated by the DNA response elements.

Pit-1, a tissue-specific POU domain transcription factor, is required for the activation of the prolactin, growth hormone, and Pit-1 promoters that confer regulation by epidermal growth factor, adenosine 3',5'-monophosphate (cAMP), and phorbol esters. Pit-1 is phosphorylated in pituitary cells at two distinct sites in response to phorbol esters and cAMP. Phosphorylation of Pit-1 modifies its conformation on DNA recognition elements and results in increased binding at certain sites and decreased binding at other sites, dependent on DNA sequences adjacent to the core Pit-1 binding motif. One residue (Thr220), located in the POU homeodomain within a sequence conserved throughout the POU-domain family, confers these responses.

Amino Acid Sequence↗

PubMed1995

Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3.

Fibroblast growth factor 4 (FGF-4) has been shown to be a signaling molecule whose expression is essential for postimplantation mouse development and, at later embryonic stages, for limb patterning and growth. The FGF-4 gene is expressed in the blastocyst inner cell mass and later in distinct embryonic tissues but is transcriptionally silent in the adult. In tissue culture FGF-4 expression is restricted to undifferentiated embryonic stem (ES) cells and embryonal carcinoma (EC) cell lines. Previously, we determined that EC cell-specific transcriptional activation of the FGF-4 gene depends on a synergistic interaction between octamer-binding proteins and an EC-specific factor, Fx, that bind adjacent sites on the FGF-4 enhancer. Through the cloning and characterization of an F9 cell cDNA we now show that the latter activity is Sox2, a member of the Sry-related Sox factors family. Sox2 can form a ternary complex with either the ubiquitous Oct-1 or the embryonic-specific Oct-3 protein on FGF-4 enhancer DNA sequences. However, only the Sox2/Oct-3 complex is able to promote transcriptional activation. These findings identify FGF-4 as the first known embryonic target gene for Oct-3 and for any of the Sox factors, and offer insights into the mechanisms of selective gene activation by Sox and octamer-binding proteins during embryogenesis.

Amino Acid Sequence↗

PubMed1996

Role of transcription factors Brn-3.1 and Brn-3.2 in auditory and visual system development.

The neurally expressed genes Brn-3.1 and Brn-3.2 (refs 1-6) are mammalian orthologues of the Caenorhabditis elegans unc-86 gene that constitute, with Brn-3.0 (refs 1-3,8,9), the class IV POU-domain transcription factors. Brn-3.1 and Brn-3.2 provide a means of exploring the potentially distinct biological functions of expanded gene families in neural development. The highly related members of the Brn-3 family have similar DNA-binding preferences and overlapping expression patterns in the sensory nervous system, midbrain and hindbrain, suggesting functional redundancy. Here we report that Brn-3.1 and Brn-3.2 critically modulate the terminal differentiation of distinct sensorineural cells in which they exhibit selective spatial and temporal expression patterns. Deletion of the Brn-3.2 gene causes the loss of most retinal ganglion cells, defining distinct ganglion cell populations. Mutation of Brn-3.1 results in complete deafness, owing to a failure of hair cells to appear in the inner ear, with subsequent loss of cochlear and vestibular ganglia.

Animals↗

PubMed2003

Activity of the Caenorhabditis elegans UNC-86 POU transcription factor modulates olfactory sensitivity.

The activity of transcription factors modulates several neural pathways that mediate complex behaviors. We describe here the role of the POU transcription factor UNC-86 in the olfactory behavior of Caenorhabditis elegans. unc-86-null mutants are defective in response to odor attractants but avoid odor repellents normally. Continuous UNC-86 activity is necessary for maintenance of odortaxis behavior; hyperactivation of UNC-86 by fusion to a VP16 activation domain dramatically enhances sensitivity to odor attractants and promotes odor-attractant adaptation. UNC-86 is not expressed in olfactory sensory neurons but is expressed throughout the life of the animal in the AIZ interneurons of the odorsensory pathway. We suggest that UNC-86 transcriptional activity regulates the expression of genes that mediate synaptic properties of AIZ and that hyperactive UNC-86::VP16 may enhance the expression of synaptic components to affect the capacity to analyze and process sensory information.

Animals↗

PubMed1999

UNC-60B, an ADF/cofilin family protein, is required for proper assembly of actin into myofibrils in Caenorhabditis elegans body wall muscle.

The Caenorhabditis elegans unc-60 gene encodes two functionally distinct isoforms of ADF/cofilin that are implicated in myofibril assembly. Here, we show that one of the gene products, UNC-60B, is specifically required for proper assembly of actin into myofibrils. We found that all homozygous viable unc-60 mutations resided in the unc-60B coding region, indicating that UNC-60B is responsible for the Unc-60 phenotype. Wild-type UNC-60B had F-actin binding, partial actin depolymerizing, and weak F-actin severing activities in vitro. However, mutations in UNC-60B caused various alterations in these activities. Three missense mutations resulted in weaker F-actin binding and actin depolymerizing activities and complete loss of severing activity. The r398 mutation truncated three residues from the COOH terminus and resulted in the loss of severing activity and greater actin depolymerizing activity. The s1307 mutation in a putative actin-binding helix caused greater activity in actin-depolymerizing and severing. Using a specific antibody for UNC-60B, we found varying protein levels of UNC-60B in mutant animals, and that UNC-60B was expressed in embryonic muscles. Regardless of these various molecular phenotypes, actin was not properly assembled into embryonic myofibrils in all unc-60 mutants to similar extents. We conclude that precise control of actin filament dynamics by UNC-60B is required for proper integration of actin into myofibrils.

Actin Depolymerizing Factors↗

PubMed1994

Short introns interrupting the Oct-2 POU domain may prevent recombination between POU family genes without interfering with potential POU domain 'shuffling' in evolution.

Transcription factors are often encoded by gene families that share the same type of DNA binding domain. The POU domain genes are one such paradigm. We compared the genomic DNA encoding the POU domain of the Oct-2 genes in human and mouse. In both species this domain is split into a cluster of four exons by short, highly diverged introns. We postulate that the main role of these introns is to prevent ectopic homologous recombination with other members of the POU gene family, with its potentially deleterious effects in somatic and germline cells. Such rapidly diverging introns may generally promote evolution by facilitating the maintenance of duplicated genes. The use of different codons for the same protein domain among members of a gene family may be a slower process that serves a similar purpose. Introns that split conserved domains such as the POU domain do not conform to the exon shuffling hypothesis originally put forward by W. Gilbert (1978). However, we note that the introns flanking the POU domain are in the same phase, i.e. interrupt codons in the same reading frame. Thus we propose that the entire POU domain, which is encoded by a tight cluster of exons, has been shuffled together during evolution as a functional unit, or 'shufflon'.

Animals↗

PubMed1990

Characterization of chicken octamer-binding proteins demonstrates that POU domain-containing homeobox transcription factors have been highly conserved during vertebrate evolution.

The DNA sequence motif ATTTGCAT (octamer) or its inverse complement has been identified as an evolutionarily conserved element in the promoter region of immunoglobulin genes. Two major DNA-binding proteins that bind in a sequence-specific manner to the octamer DNA sequence have been identified in mammalian species--a ubiquitously expressed protein (Oct-1) and a lymphoid-specific protein (Oct-2). During characterization of the promoter region of the chicken immunoglobulin light chain gene, we identified two homologous octamer-binding proteins in chicken B cells. When the cloning of the human gene for Oct-2 revealed it to be a member of a distinct family of homeobox genes, we sought to determine if the human Oct-2 cDNA could be used to identify homologous chicken homeobox genes. Using a human Oct-2 homeobox-specific DNA probe, we were able to identify 6-10 homeobox-containing genes in the chicken genome, demonstrating that the Oct-2-related subfamily of homeobox genes exists in avian species. Low-stringency screening of a chicken embryonic cDNA library allowed us to clone one of these genes. DNA sequence analysis revealed it to be the chicken homologue of the human Oct-1 gene. The predicted protein sequence of the chicken Oct-1 gene demonstrated that the gene for Oct-1 has been highly conserved during vertebrate evolution with an overall 96% amino acid sequence identity between the chicken and human proteins. The previously described POU domain (termed POU for its presence in the Pit-1, Oct-1/Oct-2, and Unc-86 genes) and homeobox domain are 100% conserved between the two protein products. Together, our data show that the POU-containing subfamily of homeobox genes have been highly conserved during vertebrate evolution, apparently as a result of selection for their DNA-binding and transcriptional regulatory properties.

Amino Acid Sequence↗

PubMed2002

Repression of Teashirt marks the initiation of wing development.

The wing imaginal disc comprises the primordia of the adult wing and the dorsal thoracic body wall. During second larval instar, the wing disc is subdivided into distinct domains that correspond to the presumptive wing and body wall. Early activity of the signaling protein Wingless has been implicated in the specification of the wing primordium. Wingless mutants can produce animals in which the wing is replaced by a duplication of thoracic structures. Specification of wing fate has been visualized by expression of the POU-homeodomain protein Nubbin in the presumptive wing territory and by repression of the homeodomain protein Homothorax. We report that repression of the zinc-finger transcription factor Teashirt (Tsh) is the earliest event in wing specification. Repression of Tsh by the combined action of Wingless and Decapentaplegic is required for wing pouch formation and for subsequent repression of Hth. Thus, repression of Tsh defines the presumptive wing earlier in development than repression of Hth, which must therefore be considered a secondary event.

Animals↗

PubMed2000

All Brn3 genes can promote retinal ganglion cell differentiation in the chick.

Targeted gene disruption studies in the mouse have demonstrated crucial roles for the Brn3 POU domain transcription factor genes, Brn3a, Brn3b, Brn3c (now called Pou4f1, Pou4f2, Pou4f3, respectively) in sensorineural development and survival. During mouse retinogenesis, the Brn3b gene is expressed in a large set of postmitotic ganglion cell precursors and is required for their early and terminal differentiation. In contrast, the Brn3a and Brn3c genes, which are expressed later in ganglion cells, appear to be dispensable for ganglion cell development. To understand the mechanism that causes the functional differences of Brn3 genes in retinal development, we employed a gain-of-function approach in the chick embryo. We find that Brn3b(l) and Brn3b(s), the two isoforms encoded by the Brn3b gene, as well as Brn3a and Brn3c all have similar DNA-binding and transactivating activities. We further find that the POU domain is minimally required for these activities. Consequently, we show that all these Brn3 proteins have a similar ability to promote development of ganglion cells when ectopically expressed in retinal progenitors. During chick retinogenesis, cBrn3c instead of cBrn3b exhibits a spatial and temporal expression pattern characteristic of ganglion cell genesis and its misexpression can also increase ganglion cell production. Based on these data, we propose that all Brn3 factors are capable of promoting retinal ganglion cell development, and that this potential may be limited by the order of expression in vivo.

Animals↗

PubMed2003

[Neurosurgical embryology. Part 1: Cell differentiation].

In pluricellular organisms, cell differentiation helps to decrease the total amount of energy needed for life. These differentiations can be evidenced at the tissular, the cellular or the molecular levels. Cell differentiation is a progressive process achieved during embryogenesis; different steps in the program can be described. One of the explanations to account for cell differentiation is the specific expression of proteins, called transcription factors, that can control the expression of selected genes. These factors are classified according to their biochemical pattern allowing description of several families of transcription factors. One of the salient questions during embryogenesis is to understand the mechanisms involved in cell differentiation. The first event is due to asymmetry of mitosis leading to the generation of two cell lineages. This is favored by the initial ovocyte polarization. The second event is due to cell interactions (namely inductions). These inductions may be explained either by cell-cell contact (favored by cell adhesion molecules) or by secreting factors that can be either hydrophilic or lipophilic.

Animals↗

PubMed2005

Axotomy-induced early down-regulation of POU-IV class transcription factors Brn-3a and Brn-3b in retinal ganglion cells.

It has been proposed that neurons being exposed to proapoptotic stimuli undergo dedifferentiation, a process that can either allow for regeneration and axon regrowth or, if remaining incomplete, can force the cell to activate apoptotic pathways. A pivotal step in the differentiation program from neuronal precursor cells to differentiated, postmitotic neurons is their exit from the cell cycle. The POU domain transcription factors Brn-3b and Brn-3a, which are expressed in retinal ganglion cells (RGCs) directly after the exit of RGC precursors from the cell cycle, can be employed as RGC-specific differentiation markers to study potential dedifferentiation of RGCs after axotomy. Here, we examined mRNAand protein expression of Brn-3a and -3b in rat RGCs following axonal lesion. We observed a rapid down-regulation of Brn-3a and -3b protein expression in axotomized RGCs, clearly preceding apoptosis of RGCs. Using real-time PCR, we show that regulation of Brn-3 expression occurred at the transcriptional level. The small subset of RGCs regenerating into a peripheral nerve graft did not (re-)express Brn-3a or -b. In conclusion, we found further evidence supporting the hypothesis of a dedifferentiation process in severed mature neurons. As Brn-3b expression has been shown to be a prerequisite for developmental survival of most RGCs and Brn-3a activates transcription of anti-apoptotic genes, down-regulation of Brn-3 transcription factors might be causally involved in the secondary death of adult RGCs following axotomy.

Animals↗

PubMed1998

Expression pattern analysis of SGF-3/POU-M1 in relation to sericin-1 gene expression in the silk gland.

Embryonic and larval expression patterns of the sericin-1 gene and its presumed transcription factor, SGF-3/POU-M1, in the silk gland were analyzed by in situ hybridization and immunohistochemistry. The sericin-1 transcripts were first detected at embryonic stage 26 in an increasing gradient pattern in the middle and posterior part of the middle silk gland (MSG), while at the same stage the SGF-3/POU-M1 was already present in the entire anterior silk gland (ASG) and in the MSG but with a decreasing gradient pattern. The latter expression pattern was consistently maintained through all larval stages, while the sericin-1 expression was detected during the feeding stages but disappeared at the molting stages. These observations suggest that, although the SGF-3/POU-M1 was proposed to be a positive transcription factor for the sericin-1 gene, the protein might function in a negative manner on sericin-1 gene transcription. Alternatively, it is also possible that the sericin-1 gene might require another unidentified factor or mediator for in vivo transcription.

Animals↗