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Results for “POU Domain Factors”

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PubMed2005

Sex, mutation and fitness: asymmetric costs and routes to recovery through compensatory evolution.

A wild-type population of Drosophila melanogaster was used to assess the impact of a known deleterious mutation, nub(1), when it had (1) evolved for up to 180 generations with the mutation or (2) recently had the same mutant allele introgressed into it. Relative to this benchmark, we observed much stronger initial fitness depression in males (-74%) than in females (-38%) and also relatively greater fitness recovery by evolved males (+55%) than females (+17%). Experimental assays revealed amelioration in both juvenile and adult fitness and suggested that the greater relative recovery of male fitness was from gains through sexual selection. These evolutionary changes in male fertility depended on pairing with their coevolved mates for both mate choice and post-copulatory components of sexual selection. Without replication at the population level, these results are used to motivate a general hypothesis rather than definitively test it: Differences in reproductive optima may generally skew mutational effects towards the more strongly sexually-selected sex due to genic capture and condition dependence.

Analysis of Variance↗
PubMedDate not supplied

Analysis of nubbin expression patterns in insects.

Previous studies have shown that the gene nubbin (nub) exhibits large differences in expression patterns between major groups of arthropods. This led us to hypothesize that nub may have evolved roles that are unique to particular arthropod lineages. However, in insects, nub has been studied only in Drosophila. To further explore its role in insects in general, we analyzed nub expression patterns in three hemimetabolous insect groups: zygentomans (Thermobia domestica, firebrat), dyctiopterans (Periplaneta americana, cockroach), and hemipterans (Oncopeltus fasciatus, milkweed bug). We discovered three major findings. First, observed nub patterns in the ventral central nervous system ectoderm represent a synapomorphy (shared derived feature) that is not present in other arthropods. Furthermore, each of the analyzed insects exhibits a species-specific nub expression in the central nervous system. Second, recruitment of nub for a role in leg segmentation occurred early during insect evolution. Subsequently, in some insect lineages (cockroaches and flies), this original role was expanded to include joints between all the leg segments. Third, the nub expression in the head region shows a coordinated change in association with particular mouthpart morphology. This suggests that nub has also gained an important role in the morphological diversification of insect mouthparts. Overall, the obtained data reveal an extraordinary dynamic and diverse pattern of nub evolution that has not been observed previously for other developmental genes.

Amino Acid Sequence↗
PubMed1998

Boundary formation in Drosophila wing: Notch activity attenuated by the POU protein Nubbin.

Cell interactions mediated by Notch-family receptors have been implicated in the specification of tissue boundaries in vertebrate and insect development. Although Notch ligands are often widely expressed, tightly localized activation of Notch is critical for the formation of sharp boundaries. Evidence is presented here that the POU domain protein Nubbin contributes to the formation of a sharp dorsoventral boundary in the Drosophila wing. Nubbin represses Notch-dependent target genes and sets a threshold for Notch activity that defines the spatial domain of boundary-specific gene expression.

Animals↗
PubMed1993

Cooperative interactions between the Caenorhabditis elegans homeoproteins UNC-86 and MEC-3.

The POU-type homeodomain protein UNC-86 and the LIM-type homeodomain protein MEC-3, which specify neuronal cell fate in the nematode Caenorhabditis elegans, bind cooperatively as a heterodimer to the mec-3 promoter. Heterodimer formation increases DNA binding stability and, therefore, increases DNA binding specificity. The in vivo significance of this heterodimer formation in neuronal differentiation is suggested by (i) a loss-of-function mec-3 mutation whose product in vitro binds DNA well but forms heterodimers with UNC-86 poorly and (ii) a mec-3 mutation with wild-type function whose product binds DNA poorly but forms heterodimers well.

Amino Acid Sequence↗
PubMed1995

The JC virus minimal core promoter is glial cell specific in vivo.

The glial cell specificity of the human papovavirus JC (JCV), an etiologic agent for progressive multifocal leukoencephalopathy, is thought to be due to the presence of both positive and negative regulatory elements upstream of the TATA region within the JCV promoter. Here we report that the JCV minimal core promoter, containing only the TATA box and an 8-bp poly(T) region immediately upstream, is sufficient to initiate transcription of an attached gene in glial cells and functions as an autonomously active initiator. We further define the sequences required for this core promoter's glial cell specificity by appropriate substitution and point mutation analysis. Ectopic expression of Tst-1, a POU domain transcription factor that has been implicated in the regulation of oligodendrocyte development, leads to higher activation of the JCV minimal core promoter in Tst-1-deficient glial cells than in non-glial HeLa cells. These results suggest a requirement for a glial cell coactivator(s) for the optimum activation of the JCV minimal core promoter by Tst-1. A discrete affinity of Tst-1 for the JCV core promoter (Kd, 1.4 x 10(-8) M) is also shown to be optimal for its promoter strength. Mutations within the core promoter that maintain this affinity for Tst-1 show maintenance of promoter strength, whereas mutants carrying a change that results in an increased affinity for Tst-1 show reduced transcriptional activity. These results suggest that moderate affinity of Tst-1 for the JCV TATA region may allow the interaction of some glial cell-specific coactivator(s) along with the basal transcription machinery to direct glial cell-specific transcription from the JCV core promoter.

Animals↗
PubMed2006

A single base difference between Pit-1 binding sites at the hGH promoter and locus control region specifies distinct Pit-1 conformations and functions.

Activation of the human growth hormone (hGH-N) gene in pituitary somatotropes is mediated by a locus control region (LCR). This LCR is composed of DNase I-hypersensitive sites (HS) located -14.5 kb to -32 kb relative to the hGH-N promoter. HSI, at -14.5 kb, is the dominant determinant of hGH-N expression and is essential for establishment of a 32-kb domain of histone acetylation that encompasses the active hGH locus. This activity is conferred by three binding sites for the POU domain transcription factor Pit-1. These Pit-1 elements are sufficient to activate hGH-N expression in the mouse pituitary. In contrast, Pit-1 sites at the hGH-N promoter are consistently unable to mediate similar activity. In the present study, we demonstrate that the functional difference between the promoter-proximal and the HSI Pit-1 binding sites can be attributed in part to a single base difference. This base affects the conformation of the Pit-1/DNA complex, and reciprocal exchange of the divergent bases between the two sets of Pit-1 elements results in a partial reversal of their transgenic activities. These data support a model in which the Pit-1 binding sites in the hGH LCR allosterically program the bound Pit-1 complex for chromatin activating functions.

Adenine↗
PubMed1993

A novel POU domain protein which binds to the T-cell receptor beta enhancer.

POU domain proteins have been implicated in the regulation of a number of lineage-specific genes. Among the first POU domain proteins described were the immunoglobulin octamer-binding proteins Oct-1 and Oct-2. It was therefore of special interest when we identified a novel lymphoid POU domain protein in Southwestern (DNA-protein) screens of T-cell lambda gt11 libraries. This novel POU protein, TCF beta 1, binds in a sequence-specific manner to a critical motif in the T-cell receptor (TCR) beta enhancer. Sequence analysis revealed that TCF beta 1 represents a new class of POU domain proteins which are distantly related to other POU proteins. TCF beta 1 is encoded by multiple exons whose organization is distinct from that of other POU domain proteins. The expression of TCF beta 1 in a tissue-restricted manner and its ability to bind to multiple motifs in the TCR beta enhancer support a role in regulating TCR beta gene expression. The expression of TCF beta 1 in both B and T cells and the ability of recombinant TCF beta 1 to bind octamer and octamer-related motifs suggest that TCF beta 1 has additional roles in lymphoid cell function. The ability of TCF beta 1 to transactivate in a sequence-specific manner is consistent with a role for regulating lymphoid gene expression.

Amino Acid Sequence↗
PubMed1995

The miti-mere and pdm1 genes collaborate during specification of the RP2/sib lineage in Drosophila neurogenesis.

We have investigated (i) the role of pdm1, a Drosophila POU gene, during the elaboration of the GMC-1-->RP2/sib lineage and (ii) the functional relationship between pdm1 and the closely linked second POU gene, miti-mere, in this lineage. We show that deletion of pdm1 causes a partially penetrant GMC-1 defect, while deletion of both miti and pdm1 results in a fully penetrant defect. This GMC-1 defect in miti- and pdm1- embryos can be rescued by the pdm1 or miti transgene. Rescue is observed only when these genes are expressed at the time of GMC-1 formation. Overexpression of pdm1 or miti well after GMC-1 is formed results in the duplication of RP2 and/or sib cells. Our results indicate that both genes are required for the normal development of this lineage and that the two collaborate during the specification of GMC-1 identity.

Animals↗
PubMed2000

Pathobiology of visceral pain: molecular mechanisms and therapeutic implications. II. Genetic approaches to pain therapy.

New analgesic drugs are necessary because a number of pain states are untreatable. Genetic approaches to the identification of analgesic drug targets include mapping genes involved in human pain perception (e.g., trkA involved in hereditary neuropathies), identifying regulators of sensory neuron function in simple multicellular organisms and then investigating the activity of their mammalian homologs (e.g., POU domain transcription factors that specify sensory cell fate), as well as difference, expression, and homology cloning of receptors, ion channels, and transcription factors present in sensory neurons. After target validation through the construction of null mutant mice, high-throughput cell-based screens can be used to identify potential drug candidates. As a result of these approaches, a number of receptors and ion channels present in sensory neurons such as voltage-gated sodium channels [sensory neuron specific (SNS) and Na channel novel] and ATP-gated (P2X3), capsaicin-gated [vanilloid receptor 1(VR1)], and proton-gated [acid-sensing ion channel (ASIC)] channels are now under investigation as potential new analgesic drug targets.

Animals↗
PubMedDate not supplied

Molecular studies of hair cell development and survival.

The development of hair cells in both the auditory and vestibular sensory epithelia is a complex process that involves the coordinated expression of many regulatory proteins. Among these is the POU-domain transcription factor Brn-3.1. This factor is expressed in hair cell precursors immediately after commitment to the hair cell fate, and continues throughout life. Deletion of this factor in mice leads to failure of hair cell differentiation during development, and to the death of a majority of the undifferentiated cells. Normal expression of Brn-3.1 is required for adult hair cell survival as well, since a mutation in this gene causes dominant, late-onset, inherited hearing loss in humans. The timing of the onset of Brn-3.1 expression suggests that factors regulating its expression may be involved in fate determination of hair cells. Moreover, genes that are themselves directly regulated by Brn-3.1 appear to play critical roles in hair cell development and survival.

Animals↗
PubMed2000

DFN2.

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Chromosome Mapping↗
PubMed1997

Molecular analysis of the POU3F4 gene in patients with clinical and radiographic evidence of X-linked mixed deafness with perilymphatic gusher.

The molecular defect in some patients with X-linked mixed deafness with perilymphatic gusher at stapes surgery (DFN3) was recently attributed to mutations in the POU3F4 gene. In this manuscript we describe the molecular analysis of the POU3F4 gene in 5 patients with clinical and radiographic evidence of DFN3. Novel mutations were found in 2 of the 5 patients analyzed, while 3 had an entirely normal protein coding sequence. The fact that 3 of the 5 patients with clinical histories and radiographic abnormalities characteristic of X-linked mixed deafness with perilymphatic gusher displayed normal POU3F4 gene sequences supports the possibility that not all patients with the characteristic phenotype have involvement of the POU3F4 gene.

Base Sequence↗
PubMed2006

Rb induces a proliferative arrest and curtails Brn-2 expression in retinoblastoma cells.

BACKGROUND: Retinoblastoma is caused by loss of the Rb protein in early retinal cells. Although numerous Rb functions have been identified, Rb effects that specifically relate to the suppression of retinoblastoma have not been defined. RESULTS: In this study, we examined the effects of restoring Rb to Y79 retinoblastoma cells, using novel retroviral and lentiviral vectors that co-express green fluorescent protein (GFP). The lentiviral vector permitted transduction with sufficient efficiency to perform biochemical analyses. Wild type Rb (RbWT) and to a lesser extent the low penetrance mutant Rb661W induced a G0/G1 arrest associated with induction of p27KIP1 and repression of cyclin E1 and cyclin E2. Microarray analyses revealed that in addition to down-regulating E2F-responsive genes, Rb repressed expression of Brn-2 (POU3F2), which is implicated as an important transcriptional regulator in retinal progenitor cells and other neuroendocrine cell types. The repression of Brn-2 was a specific Rb effect, as ectopic p27 induced a G0/G1 block, but enhanced, rather than repressed, Brn-2 expression. CONCLUSION: In addition to Rb effects that occur in many cell types, Rb regulates a gene that selectively governs the behavior of late retinal progenitors and related cells.

Cell Line, Tumor↗
PubMed2004

Sim2 contributes to neuroendocrine hormone gene expression in the anterior hypothalamus.

Paraventricular (PVN) and supraoptic nuclei of the hypothalamus maintain homeostasis by modulating pituitary hormonal output. PVN and supraoptic nuclei contain five major cell types: oxytocin-, vasopressin-, CRH-, somatostatin-, and TRH-secreting neurons. Sim1, Arnt2, and Otp genes are essential for terminal differentiation of these neurons. One of their common downstream genes, Brn2, is necessary for oxytocin, vasopressin, and CRH cell differentiation. Here we show that Sim2, a paralog of Sim1, contributes to the expression of Trh and Ss genes in the dorsal preoptic area, anterior-periventricular nucleus, and PVN. Sim2 expression overlaps with Trh- and Ss-expressing cells, and Sim2 mutants contain reduced numbers of Trh and Ss cells. Genetically, Sim1 acts upstream of Sim2 and partially compensates for the loss of Sim2. Comparative expression studies at the anterior hypothalamus at early stages reveal that there are separate pools of Trh cells with distinctive molecular codes defined by Sim1 and Sim2 expression. Together with previous reports, our results demonstrate that Sim1 and Otp utilize two common downstream genes, Brn2 and Sim2, to mediate distinctive sets of neuroendocrine hormone gene expression.

Animals↗