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PubMed2004

Specification of Drosophila motoneuron identity by the combinatorial action of POU and LIM-HD factors.

In both vertebrates and invertebrates, members of the LIM-homeodomain (LIM-HD) family of transcription factors act in combinatorial codes to specify motoneuron subclass identities. In the developing Drosophila embryo, the LIM-HD factors Islet (Tailup) and Lim3, specify the set of motoneuron subclasses that innervate ventral muscle targets. However, as several subclasses express both Islet and Lim3, this combinatorial code alone cannot explain how these motoneuron groups are further differentiated. To identify additional factors that may act to refine this LIM-HD code, we have analyzed the expression of POU genes in the Drosophila embryonic nerve cord. We find that the class III POU protein, Drifter (Ventral veinless), is co-expressed with Islet and Lim3 specifically in the ISNb motoneuron subclass. Loss-of-function and misexpression studies demonstrate that the LIM-HD combinatorial code requires Drifter to confer target specificity between the ISNb and TN motoneuron subclasses. To begin to elucidate molecules downstream of the LIM-HD code, we examined the involvement of the Beaten path (Beat) family of immunoglobulin-containing cell-adhesion molecules. We find that beat Ic genetically interacts with islet and Lim3 in the TN motoneuron subclass and can also rescue the TN fasciculation defects observed in islet and Lim3 mutants. These results suggest that in the TN motoneuron context, Islet and Lim3 may specify axon target selection through the actions of IgSF call-adhesion molecules.

Animals↗
PubMed2003

Overexpression of FABP7 in Down syndrome fetal brains is associated with PKNOX1 gene-dosage imbalance.

Suppression subtractive hybridization performed on Down syndrome (DS) fetal brains revealed a differentially expressed gene, FABP7, mapped to 6q22-23. FABP7 overexpression in DS brains was verified by real-time PCR (1.63-fold). To elucidate the molecular basis of FABP7 overexpression and establish the relationship with chromosome 21 trisomy, the FABP7 promoter was cloned by genomic inverse PCR. Comparison to the mouse ortholog revealed conservation of reported regulatory elements, among them a Pbx/POU binding site, known to be the target of PBX heteromeric complexes. PBX partners include homeobox-containing proteins, such as PKNOX1 (PREP1), a transcription factor mapping at 21q22.3. We report here: (i) overexpression of PKNOX1 in DS fetal brains; (ii) in vitro specific binding of PKNOX1 to the Pbx/POU site of the FABP7 promoter; (iii) in vivo FABP7 promoter trans-activation in cultured neuroblastoma cells caused by PKNOX1 overexpression. To our knowledge this is the first report of a direct relation between dosage imbalance of a chromosome 21 gene and altered expression of a downstream gene mapping on another chromosome. Given the role of FABP7 in the establishment, development and maintenance of the CNS, we suggest that the overexpression of FABP7 could contribute to DS-associated neurological disorders.

Animals↗
PubMed2006

Xenopus POU factors of subclass V inhibit activin/nodal signaling during gastrulation.

Three POU factors of subclass V, Oct-25, Oct-60 and Oct-91 are expressed in Xenopus oocytes and early embryos. We here demonstrate that vegetal overexpression of Oct-25, Oct-60, Oct-91 or mammalian Oct-3/4 suppresses mesendoderm formation in Xenopus embryos. Oct-25 and Oct-60 are shown to inhibit activin/nodal and FGF signaling pathways. Loss of Oct-25 and Oct-60 function results in elevated transcription of mesendodermal marker genes and ectopic formation of endoderm in the equatorial region of gastrula stage embryos. Within the ectoderm, Oct-25 promotes neural fate by upregulating neuroectodermal genes, such as Xsox2, which prevent differentiation of neural progenitors into neurons. We also show that mouse Oct-3/4 and Xenopus Oct-25 or Oct-60 behave as functional homologues. We conclude that Xenopus Oct proteins are required to control the levels of embryonic signaling pathways, thereby ensuring the correct specification of germ layers.

Activins↗
PubMed2001

The closely related POU family transcription factors Brn-3a and Brn-3b are expressed in distinct cell types in the testis.

Although the Brn-3a and Brn-3b POU family transcription factors were originally identified in neuronal cells, their expression in some non neuronal cell types has previously been reported. Here we report that Brn-3a and Brn-3b are also expressed in the testis with expression of each factor being observed at distinct stages of germ cell development. Thus, Brn-3a is expressed in spermatogonia whereas Brn-3b expression is observed in post-meiotic spermatids. In agreement with this, Brn-3a expression is detectable much earlier than that of Brn-3b in testes derived from sexually immature postnatal animals. Similarly, Brn-3b expression is absent in knock out mice lacking a functional CREM transcription factor in which the later stages of germ cell development do not occur, whereas Brn-3a expression is observed at similar levels in the testes of these knock out mice. Interestingly, the cellular pattern of Brn-3a expression during germ cell development coincides with that of the BRCA-1 anti-oncogene. Consistent with the possibility that Brn-3a may regulate expression of BRCA-1 in the testis, we have shown that Brn-3a can strongly activate the BRCA-1 promoter in co-transfection experiments whereas Brn-3b does not have this effect. Hence, as observed in neuronal cells, Brn-3a and Brn-3b may play distinct and important functional roles in the regulation of gene expression during germ cell development.

Animals↗
PubMed2004

Interplay of SOX and POU factors in regulation of the Nestin gene in neural primordial cells.

Intermediate-filament Nestin and group B1 SOX transcription factors (SOX1/2/3) are often employed as markers for neural primordium, suggesting their regulatory link. We have identified adjacent and essential SOX and POU factor binding sites in the Nestin neural enhancer. The 30-bp sequence of the enhancer including these sites (Nes30) showed a nervous system-specific and SOX-POU-dependent enhancer activity in multimeric forms in transfection assays and was utilized in assessing the specificity of the synergism; combinations of either group B1 or group C SOX (SOX11) with class III POU proved effective. In embryonic day 13.5 mouse spinal cord, Nestin was expressed in the cells with nuclei in the ventricular and subventricular zones. SOX1/2/3 expression was confined to the nuclei of the ventricular zone; SOX11 localized to the nuclei of both subventricular (high-level expression) and intermediate (low-level expression) zones. Class III POU (Brn2) was expressed at high levels, localizing to the nucleus in the ventricular and subventricular zones; moderate expression was observed in the intermediate zone, distributed in the cytoplasm. These data support the model that synergic interactions between group B1/C SOX and class III POU within the nucleus determine Nestin expression. Evidence also suggests that such interactions are involved in the regulation of neural primordial cells.

Animals↗
PubMed1999

PQBP-1, a novel polyglutamine tract-binding protein, inhibits transcription activation by Brn-2 and affects cell survival.

A novel gene, designated PQBP-1, which encodes a 265 residue protein that binds to the polyglutamine tract of the brain-specific transcription factor Brn-2, was identified. PQBP-1, which also interacts with the polyglutamine tract of triplet repeat disease gene products, binds with a higher affinity to an expanded polyglutamine tract. PQBP-1 has several functional domains, including hepta- and di-amino acid repeat sequences rich in polar residues essential for its interaction with the polyglutamine tract, a WWP/WW domain which binds to proline-rich motifs in other proteins, a putative nuclear localization signal sequence and a C2domain implicated in Ca2+-dependent phospholipid signaling. PQBP-1 is located in the nucleus and inhibits transcriptional activation by Brn-2. Overexpression of PQBP-1 in P19 embryonic carcinoma cells suppresses their growth rate and enhances their susceptibility to various stresses including serum deprivation, retinoic acid treatment and UV irradiation. Northern blot and in situ hybridization analyses revealed that PQBP-1 is a ubiquitous protein and is expressed primarily in neurons throughout the brain, with abundant levels in hippocampus, cerebellar cortex and olfactory bulb. These results suggest that PQBP-1 mediates important cellular functions under physiological and pathological conditions via its interaction with polyglutamine tracts.

Amino Acid Sequence↗
PubMed1998

Regulation of POU genes by castor and hunchback establishes layered compartments in the Drosophila CNS.

POU transcription factors participate in cell-identity decisions during nervous system development, yet little is known about the regulatory networks controlling their expression. We report all known Drosophila POU genes require castor (cas) for correct CNS expression. drifter and I-POU depend on cas for full expression, whereas pdm-1 and pdm-2 are negatively regulated. cas encodes a zinc finger protein that shares DNA-binding specificity with another pdm repressor: the gap segmentation gene regulator Hunchback (Hb). Our studies reveal that the embryonic CNS contains sequentially generated neuroblast sublineages that can be distinguished by their expression of either Hb, Pdm-1, or Cas. Hb and Cas may directly silence pdm expression in early and late developing sublineages, given that pdm-1 cis-regulatory DNA contains >=32 Hb/Cas-binding sites and its enhancer(s) are ectopically activated in cas- neuroblasts. In addition, the targeted misexpression of Cas in all neuroblast lineages reduces Pdm-1 expression without altering Hb expression. By ensuring correct POU gene expression boundaries, hb and cas maintain temporal subdivisions in the cell-identity circuitry controlling CNS development.

Animals↗
PubMed2005

Highly specific overexpression of the transcription factor SOX11 in human malignant gliomas.

Malignant glioma comprises the majority of primary human brain tumors with 16,800 new cases reported each year in the USA. Its prognosis remains dismal despite numerous attempts to improve conventional therapeutic modalities. Therefore, much effort is devoted to the exploration of alternative forms of treatment such as immunotherapy. The identification of potential target structures highly overexpressed in brain tumors is a crucial prerequisite for the activation of the immune defense against malignant glioma cells. By screening an expression database for genes highly expressed in glioblastoma multiforme (GBM), we identified the Pit-Oct-Unc (POU) cooperating transcription factor SOX11 that is known to be crucially involved in brain development. Analysis of the expression pattern of SOX11 in different normal adult and fetal tissues by multiple tissue dot blot and by a highly sensitive quantitative PCR assay confirmed the selective overexpression of SOX11 in fetal brain tissue. Examination of tissue specimens obtained from malignant gliomas and from normal brain by quantitative real-time PCR (Q-RT-PCR) revealed upregulation of SOX11 in almost all tumor samples (15/16) as compared to the pooled normal brain. Seventy-five percent of the tumor samples (12/16) showed a 5- to more than 600-fold overexpression. We conclude that, after downregulation of SOX11 in the adult brain, its expression is reactivated during tumorigenesis and that SOX11 therefore represents a promising novel molecular target for adjuvant therapy of malignant gliomas.

Brain Neoplasms↗
PubMed2001

Developmental expression of the POU transcription factor qBrn-2 during somitic myogenesis in quail.

We prepared a specific antiserum to the qBrn-2 protein and examined the developmental distribution of this protein during quail somitic myogenesis. In contrast to its mammalian homolog N-Oct-3, qBrn-2 exhibited an impressive spatio-temporal profile in somitic myogenesis, in addition to the orthodox expression observed in the developing neural tube. In somites, qBrn-2 was expressed in the outer epithelial cells, but not in the core cells. During the somite differentiation, qBrn-2 expression was enhanced and restricted to myotome. The location of qBrn-2 expression seemed to overlap with that of myf5 and myoD in myotome. However, in cells that just began to express myf5 or myoD, qBrn-2 expression was not obvious. As embryonic development proceeded, qBrn-2 positive cells in myotome migrated dorsally and ventrally, and qBrn-2 expression was still observed at dorsal and ventral muscle masses in the forelimb. On the basis of our observations, it seems that qBrn-2 may play important roles in the determination, differentiation and migration of muscle precursor cells, in addition to its known roles in neurogenesis.

Animals↗
PubMed1997

A single residue within the homeodomain of the Brn-3 POU family transcription factors determines whether they activate or repress the SNAP-25 promoter.

The closely related POU family transcription factors Brn-3a and Brn-3b differ in their effect on a number of different neuronally expressed promoters such as that of the gene encoding the synaptic vesicle component SNAP-25. Thus Brn-3a activates these promoters whilst Brn-3b represses both their basal activity and their activation by Brn-3a. We show here that alterations of a single amino acid at position 22 in the POU-homeodomain from the isoleucine found in Brn-3b to the valine found at the equivalent position in Brn-3a converts Brn-3b from a repressor to an activator of the SNAP-25 gene promoter. The converse mutation in Brn-3a abolishes its ability to activate the SNAP-25 gene promoter and allows it to repress the basal activity of the promoter and its activation by wild type Brn-3a. This is the first time that a single amino acid change has been shown to convert an activator of a naturally occurring promoter to a repressor and vice versa. These results are discussed in terms of the critical role of position 22 in the POU homeodomain in the protein-protein interactions of POU proteins.

Biotransformation↗
PubMed1997

Multiple promoter elements differentially regulate the expression of the mouse tenascin gene.

Tenascin (TN) is an extracellular matrix glycoprotein that is expressed in a characteristic spatiotemporal pattern during development and is up-regulated in the adult during tumorigenesis, wound healing, and nerve regeneration. In previous studies, we identified a promoter within the proximal 250 bp upstream of the mouse TN gene that contains several putative regulatory elements that are conserved among vertebrate TN genes. We have identified four different DNA elements within this promoter and show that they contribute in different ways to TN gene expression in NIH 3T3 fibroblasts, C6 glioma cells, and N2A neuroblastoma cells. These elements comprise a binding site for Krox proteins, one for nuclear factor 1, an octamer motif that binds POU-homeodomain proteins, and a novel TN control element. The nuclear factor 1 and TN control element had positive effects on TN promoter activity and formed similar DNA-protein complexes with nuclear extracts from all three cell lines. The Krox element had a negative effect on TN promoter activity in N2A cells, a positive effect in C6 cells, and no effect in NIH 3T3 cells. Two DNA binding complexes, one correlated with the negative and the other with the positive activities of the Krox element, were found to contain the protein Krox24. In cotransfection experiments, the octamer motif was required for induction of TN promoter activity by the POU-homeodomain protein Brn2 in N2A cells but was inactive in C6 cells. Consistent with these findings, N2A cells transfected with Brn2 formed octamer-binding complexes containing N-Oct3, the transcriptionally active form of Brn2, whereas complexes formed in C6 cells contained only N-Oct5A and N-Oct5B. Our results provide a striking example of the diversity of regulatory mechanisms that can be called forth by combining different promoter motifs with transcriptional activators or repressors.

3T3 Cells↗
PubMed2003

OBF1 enhances transcriptional potential of Oct1.

The POU transcription factors Oct1 and Oct2 bind to DNA in various monomer and dimer configurations. Depending on the DNA sequence to which they bind, the dimers are arranged in configurations that are either accessible (PORE sequence) or inaccessible (MORE sequence) to the B-cell-specific cofactor OBF1 (OcaB, Bob1). As shown previously, the MORE and related sequences (such as the heptamer/octamer motif) are found in immunoglobulin heavy chain promoters. Here we show that the expression of Osteopontin, which contains a PORE sequence in its enhancer region, depends on the presence of OBF1 in B cells. OBF1 alleviates DNA sequence requirements of the Oct1 dimer on PORE-related sequences in vitro. Furthermore, OBF1 stabilizes POU dimer-DNA interactions and overrides Oct1 interface mutations, which abolish PORE-mediated dimerization without OBF1. Our data indicate that the PORE-type Oct1 or Oct2 dimer, rather than the monomer, is the primary target of the cofactor OBF1. Based on our biochemical data, we propose a mode of OBF1-Oct1 dimer interaction, suggesting a novel arrangement of the subdomain connectivities.

B-Lymphocytes↗
PubMed2002

Late-onset hearing loss in a mouse model of DFN3 non-syndromic deafness: morphologic and immunohistochemical analyses.

Recently, we reported that homozygous males and females of a mouse model of DFN3 non-syndromic deafness generated by the deletion of Brn-4 transcription factor showed profound deafness due to severe alterations in the cochlear spiral ligament fibrocytes from the age of 11 weeks, whereas no hearing loss was recognized in young female heterozygotes. It is known that a part of obligate female carriers of DFN3 showed progressive hearing loss. In the present study, we examined the late-onset effect of Brn-4 deficiency on the hearing organ of the mouse. About one third of heterozygous female mice revealed late-onset profound deafness at the age of 1 year. Furthermore, in these deafened heterozygotes, characteristic abnormalities in Reissner's membrane attachment and type II fibrocytes in the suprastrial zone became evident under light microscope, similar to homozygous female mice. A significant reduction in the immunoreactivity of connexin 26 (Cx26), connexin 31 (Cx31), Na,K-ATPase and Na-K-Cl cotransporter in the spiral ligament fibrocytes was observed in aged heterozygotes showing late-onset profound deafness. The late-onset phenotype observed in heterozygous mutant mice, being consistent with the progressive deafness observed in human female heterozygotes, may be explained by alterations of the ion transport systems in the spiral ligament fibrocytes.

Age of Onset↗
PubMed2006

Aberrant promoter methylation and silencing of the POU2F3 gene in cervical cancer.

POU2F3 (OCT11, Skn-1a) is a keratinocyte-specific POU transcription factor whose expression is tied to squamous epithelial stratification. It is also a candidate tumor suppressor gene in cervical cancer (CC) because it lies in a critical loss of heterozygosity region on 11q23.3 in that cancer, and its expression is lost in more than 50% of CC tumors and cell lines. We now report that the loss of POU2F3 expression is tied to the hypermethylation of CpG islands in the POU2F3 promoter. Bisulfite sequencing analysis revealed that methylation of specific CpG sites (-287 to -70 bp) correlated with POU2F3 expression, which could be reactivated with a demethylating agent. Combined bisulfite restriction analysis revealed aberrant methylation of the POU2F3 promoter in 18 of 46 (39%) cervical tumors but never in normal epithelium. POU2F3 expression was downregulated and inversely correlated with promoter hypermethylation in 10 out of 11 CC cell lines. Immunohistochemical analysis on a cervical tissue microarray detected POU2F3 protein in the epithelium above the basal layer. As the disease progressed, expression also decreased, especially in invasive squamous cell cancer (70% loss). Thus, aberrant DNA methylation of the CpG island in POU2F3 promoter appears to play a key role in silencing this gene expression in human CC. The results suggested that POU2F3 might be one of the CC-related tumor suppressor genes, which are disrupted by both epigenetic and genetic mechanisms.

Adenocarcinoma↗
PubMed2006

The murine Pou6f2 gene is temporally and spatially regulated during kidney embryogenesis and its human homolog is overexpressed in a subset of Wilms tumors.

We have previously suggested the transcription factor gene POU6F2 as a novel tumor suppressor involved in Wilms tumor (WT) predisposition. Since WT arises from pluripotent embryonic renal precursors, in this study we analyzed the expression of the murine homolog Pou6f2 during kidney embryogenesis and compared it to that of Wt1, the homolog of WT1, a known WT related gene involved in mesenchyme to epithelium conversion. Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) performed for Pou6f2 on kidney specimens from embryos, pups, and adult mice, showed that the Pou6f2 mRNA was more abundant in the earliest analyzed phase of kidney organogenesis (E13) than in more advanced fetal stages and in adult animal. In situ RT-PCR demonstrated that Pou6f2 expression parallels the centripetal differentiation of renal morphogenesis. In addition, in E18 kidney, most structures exhibiting Pou6f2 expression stained positively in immunohistochemistry for the Wt1 protein. Finally, quantitative real-time RT-PCR revealed an overexpression (>/=80 times) of POU6F2 compared with normal kidney in 5 of 22 (23%) WTs. The finding of a highly regulated temporal and spatial Pou6f2 expression during renal organogenesis, of its coexpression with Wt1 and of POU6F2 overexpression in a subset of WTs are consistent with a role of POU6F2 in kidney development and provide further support to its involvement in WT.

Adult↗
PubMed2005

Abnormal mesenchymal differentiation in the superior semicircular canal of brn4/pou3f4 knockout mice.

OBJECTIVE: To examine the developmental time course of the mutant phenotype and cellular mechanisms that result in malformations of the superior semicircular canal (SSCC) in Brn4 knockout mice. Mutations in the Brn4/Pou3f4 gene result in characteristic inner ear abnormalities in mutant mouse pedigrees, and the findings in these mice are similar to those in human X-linked deafness type III. DESIGN: Mutant and control mice were killed at various neonatal time points to assess the development of the SSCC. Measurements of SSCC diameter were made on paint-perfused specimens at postnatal day (P) 0, P7, P10, and P14. Histologic evaluation of the SSCC was made on hematoxylin-eosin-stained sections at P10. RESULTS: A dysmorphic constriction of the superior arc of the SSCC in Brn4 knockout mice was initially detectable at P14. Interestingly, the mutant SSCC is indistinguishable from control mice at earlier neonatal time points. In mutant neonates, there is persistence of immature woven bone with high cellularity surrounding the perilymphatic space of the SSCC. These findings are not present in control animal specimens, which demonstrate appropriate lamellar bony architecture. CONCLUSIONS: In Brn4 knockout mice, constriction of the SSCC with narrowing of the bony labyrinth develops in the postnatal period at approximately P14. The persistence of immature bone in affected mice indicates that signaling abnormalities disrupt normal mesenchymal differentiation in the SSCC.

Animals↗
PubMed2005

Deletion of and novel missense mutation in POU3F4 in 2 families segregating X-linked nonsyndromic deafness.

OBJECTIVE: To analyze the physical manifestations and genetic features of 2 families segregating X-linked deafness, which is most commonly reported to be caused by mutations of the POU domain gene POU3F4 at the DFN3 locus. DESIGN: Computed tomographic study of the temporal bone in probands from each family, followed by mutation screening and deletion mapping of POU3F4 in family members. SETTING: Two midwestern genetics clinics. PARTICIPANTS: Two families with X-linked deafness. MAIN OUTCOME MEASURES: Anomalies of the inner ear in the probands; results of gene mapping and severity and effects of hearing loss in the family members. RESULTS: In the first family, a large deletion was identified that includes POU3F4 and extends upstream approximately 530 kilobases; in the second family, a novel serine-to-leucine (S228L) amino acid mutation was identified in the POU-specific domain of POU3F4. Both the deletion and the missense mutation segregate with the clinical phenotype and are causally related to the deafness in these families. CONCLUSIONS: Deafness related to the POU3F4 gene is associated with dilation of the internal auditory canal and a spectrum of other temporal bone anomalies that range in severity from mild to severe dysplasia of the cochlea and semicircular canals. The consequence of these anomalies is a congenital mixed hearing loss, the sensorineural component of which progresses over time. Affected males can also present with vestibular dysfunction that is associated with delayed developmental motor milestones. Intrafamilial variability occurs.

Chromosome Deletion↗
PubMed1996

Sequence and analysis of a 26.9 kb fragment from chromosome XV of the yeast Saccharomyces cerevisiae.

We have determined the nucleotide sequence of a fragment of chromosome XV of Saccharomyces cerevisiae cloned into cosmid pEOA048. The analysis of the 26,857 bp sequence reveals the presence of 19 open reading frames (ORFs), and of one RNA-coding gene (SNR17A). Six ORFs correspond to previously known genes (MKK1/SSP32, YGE1/GRPE/MGE1, KIN4/KIN31/KIN3, RPL37B, DFR1 and HES1, respectively), all others were discovered in this work. Only five of the new ORFs have significant homologs in public databases, the remaining eight correspond to orphans (two of them are questionable). O5248 is a probable folypolyglutamate synthetase, having two structural homologs already sequenced in the yeast genome. O5273 shows homology with a yeast protein required for vanadate resistance. O5268 shows homology with putative oxidoreductases of different organisms. O5257 shows homology with the SAS2 protein and another hypothetical protein from yeast. The last one, O5245, shows homology with a putative protein of Caenorhabditis elegans of unknown function. The present sequence corresponds to coordinates 772,331 to 799,187 of the entire chromosome XV sequence which can be retrieved by anonymous ftp (ftp. mips. embnet. org).

Agglutinins↗