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Results for “POU Domain Factors”

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PubMed2000

Cross-regulatory interactions among tracheal genes support a co-operative model for the induction of tracheal fates in the Drosophila embryo.

The Drosophila tracheal system arises from clusters of ectodermal cells that invaginate and migrate to originate a network of epithelial tubes. Genetic analyses have identified several genes that are specifically expressed in the tracheal cells and are required for tracheal development. Among them, trachealess (trh) is able to induce ectopic tracheal pits and therefore it has been suggested that it would act as an inducer of tracheal cell fates; however, this capacity appears to be spatially restricted. Here we analyze the expression of the tracheal specific genes in the early steps of tracheal development and their cross-interactions. We find that there is a set of primary genes including trh and ventral veinless (vvl) whose expression does not depend on any other tracheal gene and a set of downstream genes whose expression requires different combinations of the primary genes. We also find that the combined expression of primary genes is sufficient to induce some downstream genes but not others. These results indicate that there is not a single master gene responsible for the appropriate expression of the tracheal genes and support a model where tracheal cell fates are induced by the co-operation of several factors rather than by the activity of a single tracheal inducer.

Animals↗

PubMed1996

The ability of POU family transcription factors to activate or repress gene expression is dependent on the spacing and context of their specific response elements.

The different forms of the Oct-2 and Brn-3 POU family transcription factors can have distinct effects on their target promoters involving both the activation and repression of gene expression. To investigate the requirements for these effects we have altered both the context and spacing of the two TAATGARAT binding sites for these factors within the herpes simplex virus immediate-early 3 gene promoter. We show that the activation of this promoter by Brn-3a and its repression by Brn-3b is dependent on the correct spacing of these binding sites. In contrast, repression of the promoter by Oct-2.4 and Oct-2.5 is dependent on both the spacing and context of these sites with the requirements for repression by Oct-2.4 or Oct-2.5 being different. These effects are discussed in the context of the mechanisms by which POU factors activate or repress their target genes.

Animals↗

PubMed2004

High affinity binding of Dab1 to Reelin receptors promotes normal positioning of upper layer cortical plate neurons.

The positions of neurons in the neocortex, hippocampus, cerebellum and various other laminated brain regions are regulated by a signaling pathway initiated by the secreted protein Reelin and requiring the intracellular adaptor protein Dab1. Dab1 and the Reelin receptors VLDLR and ApoER2 are expressed by neurons whose migrations are coordinated by Reelin. In vitro, Dab1 binds with high affinity to the cytoplasmic tails of VLDLR and ApoER2 via its PTB domain. To test the importance of Dab1 binding to VLDLR and ApoER2, we replaced the Dab1 gene with a cDNA cassette encoding a point mutant allele, Dab1(F158V). This mutation strongly decreases Dab1 binding in vitro to peptides containing the ApoER2 or VLDLR cytoplasmic regions. Surprisingly, Dab1(F158V/F158V) homozygotes have no discernable phenotype. However, Dab1(F158V/-) hemizygous animals have a subtle phenotype in which late-generated cortical plate neurons migrate excessively into the marginal zone. Early cortical plate neurons, subplate neurons, hippocampal pyramidal cells and cerebellar Purkinje cells are positioned normally. Thus Dab(F158V) is a weak loss-of-function (hypomorphic) allele that has no detectable effect when homozygous. The phenotype of Dab1(F158V/-) hemizygotes shows that late cortical plate neurons of layers 2-3 require efficient Reelin-Dab1 signaling to prevent them entering the marginal zone. The Dab1(F158V) allele adds to a series of Dab1 alleles that demonstrates cell type-specific variation in the Reelin-Dab1 pathway.

Age Factors↗

PubMed1996

Promoter sequences for the establishment of mec-3 expression in the nematode Caenorhabditis elegans.

In certain stereotyped lineages of Caenorhabditis elegans, the mec-3 gene is transcribed in neurons that are anterior daughters of cells containing the UNC-86 protein. UNC-86 binds to the mec-3 promoter and is necessary for transcription activation, but this protein is present in many cells that do not transcribe mec-3, including the posterior sister and parent cells of the mec-3 expressing neurons. To understand how the mec-3 promoter directs transcription in only a subset of cells that contain UNC-86, we have compared sequences within the promoter that are bound by UNC-86 in vitro with sequences that are necessary for early transcription of mec-3 in vivo. We find that upstream of the mec-3 start codon are two blocks of sequence that are each sufficient to generate the cellular pattern of mec-3 transcription. The proximal sequence includes three previously identified short regions that have been conserved in nematode evolution and each contains one high-affinity UNC-86 binding site. The recognition consensus sequence for UNC-86 is CATnnnT/AAAT, which is identical to the recognition sequence for the UNC-86-related mammalian transcription factor Brn-3. Adjacent to the UNC-86 recognition site is an additional sequence that is important for establishment of mec-3 expression and is presumably recognized by an unidentified transcription factor.

Amino Acid Sequence↗

PubMed2003

Adenoviral-mediated over-expression of Brn2 in the rat paraventricular nucleus: no effect on vasopressin or corticotrophin releasing factor RNA levels.

We have used an over-expression strategy to test the hypothesis that the Class III POU transcription factor Brn2 is rate limiting in the control of the level of expression of the vasopressin (VP) gene in the paraventricular nucleus of the rat hypothalamus. Knockout studies in mice have suggested that Brn2 may contribute to the control of the level of VP gene expression in the adult hypothalamus. However, we show here that in heterologous cell lines, Brn2 transactivates neither the proximal promoter of the rat VP gene, nor a novel reporter construct consisting of the rat VP structural gene and 3 and 2 kbp of upstream and downstream flanking sequences. We hypothesised that this maybe due either to the lack of cis-acting elements within the confines of the reporter vectors used, or to the absence in heterologous cells, of factors required for Brn2 activity. As no cell lines exist that correspond to VP neurons, we devised an adenoviral vector delivery strategy that enabled efficient over-expression of Brn2 in the paraventricular nucleus of the intact rat. Localised over-expression of Brn2 had no effect on VP hnRNA levels. Neither did we detect corticotrophin releasing factor (CRF) mRNA up-regulation by Brn2 over-expression in vivo. This was unexpected as Brn2 transactivates the proximal CRF promoter in vitro. Whilst Brn2 is required for the development of the hypothalamic structures that express VP and CRF, these data suggest that this transcription factor is not required, or is not rate limiting, for expression in the adult.

Adenoviridae↗

PubMed1996

Class III POU genes of zebrafish are predominantly expressed in the central nervous system.

POU genes encode a family of transcription factors involved in a wide variety of cell fate decisions and in the regulation of differentiation pathways. We have searched for POU genes in the zebrafish, a popular model organism for the study of early development of vertebrates. Besides five putative pseudogenes we have identified five POU genes that are expressed during embryogenesis. Probes obtained by PCR were used to isolate full-length cDNAs. Four of the isolated genes encode proteins with class III POU domains. Analysis of genomic clones suggests that the fish genes in general do not contain introns, similar to class III genes of mammals. However, the C-termini of two of the encoded proteins vary due to facultative splicing of a short intervening sequence. These two genes show very strong similarities in their sequence. They have probably arisen by gene duplication, possibly as part of a larger scale duplication of part of the zebrafish genome. Analysis of the expression of the class III genes shows that they are predominantly expressed in the central nervous system and that they may play important roles in patterning the embryonic brain.

Amino Acid Sequence↗

PubMed1995

Identification of a sequence-specific single-stranded DNA binding protein that suppresses transcription of the mouse myelin basic protein gene.

The myelin basic protein (MBP) gene is expressed only in oligodendrocytes and Schwann cells, and expression follows a tightly regulated developmental time course. Cell type- and developmental stage-specific expression of the MBP gene appears to be regulated by a series of cis-acting elements located upstream of the transcription start site. The proximal element of the MBP regulatory region (MB1), located between nucleotides -14 and -50, is one of several elements participating in the programmed expression of MBP. In this report, we describe the molecular cloning and characterization of myelin gene expression factor-2 (Myef-2), a protein isolated from mouse brain that binds specifically to single-stranded DNA derived from the MB1 element and represses transcription of the MBP gene in transient transfection assay. Myef-2 mRNA is developmentally regulated in mouse brain; its peak expression occurs at postnatal day 7, prior to the onset of MBP expression. The developmental pattern of Myef-2 mRNA expression coincides with that previously described for SCIP, a POU domain transcription factor that also represses myelin basic protein expression. The myef-2 gene maps to mouse chromosome 2. The relevance of these findings for regulation of MBP gene expression and oligodendrocyte differentiation is discussed.

Aging↗

PubMed1999

A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1beta.

Mutations in the homeodomain-containing transcription factor hepatocyte nuclear factor (HNF)-1beta are the cause of one form of maturity-onset diabetes of the young (MODY), type 5 (MODY5). We have studied a Norwegian family, N5, with a syndrome of mild diabetes, progressive non-diabetic renal disease and severe genital malformations. The sequence of the HNF-1beta gene ( TCF2 ) revealed a 75 bp deletion in exon 2 (409-483del) which would result in the synthesis of a protein lacking amino acids Arg137 to Lys161 (R137-K161del). This deletion is located in the pseudo-POU region of HNF-1beta, a region implicated in the specificity of DNA binding. Functional studies of R137-K161del HNF-1beta revealed that it could not bind an HNF-1 target sequence or stimulate transcription of a reporter gene indicating that this is a loss-of-function mutation. The R137-K161del allele co-segregated with diabetes and renal disease in pedigree N5. In addition, two of four female carriers with this mutation had vaginal aplasia and rudimentary uterus (Müllerian aplasia). These studies strongly suggest that heterozygous mutations in the HNF-1beta gene are associated with a syndrome characterized by MODY and severe, non-diabetic renal disease. Moreover, the presence of internal genital malformations in two females suggests that additional clinical features may be associated with HNF-1beta mutations.

Adolescent↗

PubMed2005

Fezl is required for the birth and specification of corticospinal motor neurons.

The molecular mechanisms controlling the differentiation of neural progenitors into distinct subtypes of neurons during neocortical development are unknown. Here, we report that Fezl is required for the specification of corticospinal motor neurons and other subcerebral projection neurons, which are absent from Fezl null mutant neocortex. There is neither an increase in cell death in Fezl(-/-) cortex nor abnormalities in migration, indicating that the absence of subcerebral projection neurons is due to a failure in fate specification. In striking contrast, other neuronal populations in the same and other cortical layers are born normally. Overexpression of Fezl results in excess production of subcerebral projection neurons and arrested migration of these neurons in the germinal zone. These data indicate that Fezl plays a central role in the specification of corticospinal motor neurons and other subcerebral projection neurons, controlling early decisions regarding lineage-specific differentiation from neural progenitors.

Age Factors↗

PubMed1999

Examination of POU homeobox gene expression in human breast cancer cells.

Abnormal expression of homeobox genes may lead to the development of leukemias, lymphomas, and solid tumors. Expression of homeobox genes in mammary glands, however, has not been studied actively until recently. We have examined the expression of POU homeobox genes in human breast cancer cell lines and human breast tissue samples. Using a pair of degenerate primers for reverse transcription-polymerase chain reaction (RT-PCR) followed by DNA sequencing, we found that the human breast cancer cell line, MCF7, expresses at least 4 POU gene products: OCT1, OCT2, OCT3 and OCT11 (Skn-1a/i, Epoc-1). The expression of OCT1 and OCT2 in other human breast epithelial cell lines was further determined by Western blot analyses and electrophoretic mobility shift assay. We were unable to detect OCT11 in human breast cancer cell lines using the anti rat Skn-1a/i antibody, although the expression of this gene in both human breast cancer cell lines and human primary breast tumors was detected by RT-PCR. OCT3 is an embryonic transcription factor. We found that this gene is also expressed in human breast cancer cell lines and all human primary breast carcinomas examined, but not in normal human breast tissue. Taken together, we have shown that several POU genes are expressed in human breast epithelial cells. As OCT3 expression was detected only in the breast cancerous cells, this embryonic transcription factor could play an important role in mammary gland carcinogenesis.

Amino Acid Sequence↗

PubMed1995

Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4.

Deafness with fixation of the stapes (DFN3) is the most frequent X-linked form of hearing impairment. The underlying gene has been localized to a 500-kilobase segment of the Xq21 band. Here, it is reported that a candidate gene for this disorder, Brain 4 (POU3F4), which encodes a transcription factor with a POU domain, maps to the same interval. In five unrelated patients with DFN3 but not in 50 normal controls, small mutations were found that result in truncation of the predicted protein or in nonconservative amino acid substitutions. These findings indicate that POU3F4 mutations are a molecular cause of DFN3.

Amino Acid Sequence↗

PubMed2003

Neuron cell type-specific SNAP-25 expression driven by multiple regulatory elements in the nematode Caenorhabditis elegans.

In order to characterize the mechanisms regulating neuronal expression of the nematode SNAP-25 gene, we identified the SNAP-25 genes of Caenorhabditis elegans and Caenorhabditis briggsae. Comparative sequence analysis and reporter assays revealed two putative 5' regulatory elements, P1 and P2, and four elements, I1h, I1m, I2h, and I2m, in the first intron. Nuclear extracts contained activities that bound the P2 and I1h elements. Different elements were required for SNAP-25 expression in different neuronal subsets; P1 was required in DA and DD motor neurons, and I1m and I2m were required in DB and DA neurons, respectively. P2 was active in amphid and phasmid neurons, I1h in pharyngeal neurons, and I2h in touch receptor neurons. The I2h element contained a putative binding site for transcription factor UNC-86. Both UNC-86 and MEC-3 were required for I2h activity in the mechanosensory neurons: in these neurons, GFP expression driven by I2h was abolished in animals bearing either an unc-86 null or a mec-3 null mutation, or an unc-86 mutation that leads to defective interaction with MEC-3. Deletion of the MEC-3 binding site also abolished the GFP expression. Gel mobility-shift assay results suggest that transcriptional regulation of SNAP-25 may involve multiple transcription factors.

Amino Acid Sequence↗

PubMed2003

[Clinical and molecular genetic analysis of monozygotic twins displaying stapes gusher syndrome (DFN3)].

BACKGROUND: DFN3 ( "stapes gusher") is the most frequent form of X-linked hearing impairment. It accounts for up to 0.5% of all cases of severe childhood hearing disorders. PATIENTS AND METHODS: Monozygotic twins with suspected stapes gusher syndrome, their mother, and control individuals were analyzed clinically and genetically. RESULTS: The clinical investigations confirmed a DFN3 phenotype in both brothers who displayed all typical symptoms. A molecular genetic investigation of the POU3F4 gene, which plays an essential role in the development of DFN3, was also performed. No chromosomal aberrations within the coding region of POU3F4were detected. Since several authors have described mutations in the 5' untranslated region of the gene also resulting in a DFN3 phenotype, we screened this area by microsatellite analysis and detected a double deletion localized in the critical interval. This is the first description of a double deletion in the non-coding region of POU3F4 leading to DFN3 phenotype. CONCLUSION: Interestingly, in spite of having an identical genotype, the twins displayed significant phenotypic differences. This underlines the importance of exogenous factors in the development of inherited pathological processes.

Audiometry, Pure-Tone↗

PubMed2005

ventral veins lacking is required for specification of the tritocerebrum in embryonic brain development of Drosophila.

The homeotic or Hox genes encode a network of conserved transcription factors which provide axial positional information and control segment morphology in development and evolution. During embryonic brain development of Drosophila, the Hox gene labial (lab) is essential for tritocerebral neuromere specification; lab loss of function results in tritocerebral cells that fail to adopt a neuronal identity, causing axonal pathfinding defects. Here we present evidence that the POU-homeodomain DNA-binding protein ventral veins lacking (vvl) acts genetically downstream of lab in the specification of the tritocerebral neuromere. In the embryonic brain, vvl expression is seen in all brain neuromeres, including the tritocerebral lab domain. Lab mutant analysis shows that vvl expression in the tritocerebrum is dependent on lab activity. Loss-of-function analysis focussed on the tritocerebrum reveals that inactivation of vvl results in patterning defects which are comparable to the brain phenotype caused by null mutation of lab. In the absence of vvl, mutant tritocerebral cells are generated and positioned correctly, but these cells fail to express neuronal markers indicating defects in neuronal differentiation. Moreover, longitudinal axon pathways in the tritocerebrum are severely reduced or absent and the tritocerebral commissure is missing in the vvl mutant brain. Genetic rescue experiments show that vvl is able to partially replace lab in the specification of the tritocerebral neuromere. Our results indicate that vvl acts downstream of the Hox gene lab and regulates specific aspects of neuronal differentiation within the tritocerebral neuromere during embryonic brain development of Drosophila.

Animals↗

PubMed2004

The Caenorhabditis elegans aryl hydrocarbon receptor, AHR-1, regulates neuronal development.

The mammalian aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxic effects of dioxins and related compounds. Dioxins have been shown to cause a range of neurological defects, but the role of AHR during normal neuronal development is not known. Here we investigate the developmental functions of ahr-1, the Caenorhabditis elegans aryl hydrocarbon receptor homolog. We show that ahr-1:GFP is expressed in a subset of neurons, and we demonstrate that animals lacking ahr-1 function have specific defects in neuronal differentiation, as evidenced by changes in gene expression, aberrant cell migration, axon branching, or supernumerary neuronal processes. In ahr-1-deficient animals, the touch receptor neuron AVM and its sister cell, the interneuron SDQR, exhibit cell and axonal migration defects. We show that dorsal migration of SDQR is mediated by UNC-6/Netrin, SAX-3/Robo, and UNC-129/TGFbeta, and this process requires the functions of both ahr-1 and its transcription factor dimerization partner aha-1. We also document a role for ahr-1 during the differentiation of the neurons that contact the pseudocoelomic fluid. In ahr-1-deficient animals, these neurons are born but they do not express the cell-type-specific markers gcy-32:GFP and npr-1:GFP at appropriate levels. Additionally, we show that ahr-1 expression is regulated by the UNC-86 transcription factor. We propose that the AHR-1 transcriptional complex acts in combination with other intrinsic and extracellular factors to direct the differentiation of distinct neuronal subtypes. These data, when considered with the neurotoxic effects of AHR-activating pollutants, support the hypothesis that AHR has an evolutionarily conserved role in neuronal development.

Animals↗

PubMed2005

Cell-type specific regulation of serotonergic identity by the C. elegans LIM-homeodomain factor LIM-4.

How a common neurotransmitter phenotype specified in neurons of different origins is an outstanding issue in neuronal development and function. In C. elegans larvae, serotonin is synthesized in 2 pairs of neurons, the secretory neurons NSM and the chemosensory neurons ADF. In order to delineate the molecular mechanisms of serotonergic phenotype establishment, we have screened for neuron-specific serotonin deficient (nss) mutants. Our prior study showed that the POU-homeodomain factor UNC-86 is expressed in and required for the NSM neurons to adopt serotonergic phenotype and correct pathfinding, whereas ADF are unaffected in unc-86-null mutants. Here, we report that the LIM-homeodomain factor LIM-4 regulates ADF serotonergic phenotype. In lim-4 mutants, many aspects of ADF differentiation occur, however, they fail to express serotonin phenotype and exhibit aberrant cilia properties. LIM-4 expression rises in the neuroblast that produces two distinct neurons: ADF and the olfactory neuron AWB. We show that lim-4 is regulated by separable mechanisms to determine disparate subtype identities in these two neuronal types. In vivo promoter analyses reveal that cis-element(s) within introns are necessary and sufficient to direct lim-4 to specify serotonergic phenotype, whereas its 5'-upstream sequence directs lim-4 function in AWB. Thus, a transcription factor may act independently to specify distinct differentiation traits in two sister cells. We propose that serotonergic identity is specified in cell-specific contexts to coordinate the development and function.

Animals↗

PubMed2006

Expression of AmphiPOU-IV in the developing neural tube and epidermal sensory neural precursors in amphioxus supports a conserved role of class IV POU genes in the sensory cells development.

POU genes play a prominent role in the nervous system differentiation of several organism models, and in particular, they are involved in the differentiation of sensory neurons in numerous invertebrate and vertebrate species. In the present report, cloning and expression profile of a class IV POU gene in amphioxus was assessed for understanding its role in the sensory systems development. A single class IV gene, AmphiPOU-IV was isolated from the amphioxus Branchiostoma floridae. From a phylogenetic point of view, AmphiPOU-IV appears to be strictly related to the vertebrate one, sharing a high homology ratio especially with all vertebrate POU-IV proteins Brn-3a, Brn-3b, and Brn-3c. AmphiPOU-IV was found in the most anterior neural plate and in scattered ectodermic cells on the flanks of neurula, such ectodermic cells resemble the characteristic morphology and position of AmphiCoe and AmphiTrk developing sensory cells. Later on, the expression was confined in some motoneurons at level of the PMC and in some segmental arranged motoneurons in the hindbrain. Such expression is also maintained in larvae, and a new site of AmphiPOU-IV expression was also found in rostrum and mouth edge epidermal sensory cells of the larva. In conclusion, our data suggest an evolutionary conserved role of POU-IV transcription factors in the specification and differentiation of the sensory system in both vertebrates and invertebrates and underline the importance of amphioxus as linking step between them.

Amino Acid Sequence↗

PubMedDate not supplied

Regulation of DNA virus transcription by cellular POU family transcription factors.

In the same way as other viral functions, the transcription of viral genes is frequently controlled by cellular regulatory proteins either acting alone or together with virally encoded factors. In this review, I discuss three examples of such regulation in different types of DNA viruses by different members of the POU family of transcription factors, all of which involve viruses which play a role in the aetiology of specific human diseases. These are the glial cell-specific transcription of JC virus which is controlled by the glial cell specific POU factor Tst-1; the regulation of human papillomavirus gene expression in the cervix by positively and negatively acting POU factors and the manner in which the balance between lytic or latent infection with HSV is controlled by positively and negatively acting POU factors which differ in their ability to interact with the virally encoded transactivator VP16. As well as being of interest in themselves, these processes may offer a therapeutic target for controlling the diseases caused by these very different viruses.

Amino Acid Sequence↗