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Michael G Rosenfeld - One of the best experts on this subject based on the ideXlab platform.
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transcriptional regulation of cortical neuron migration by POU Domain factors
Science, 2002Co-Authors: Robert J. Mcevilly, Marcus D. Schonemann, Farideh Hooshmand, Marcela Ortiz De Diaz, Michael G RosenfeldAbstract:The identification of pathways mediated by the kinase Cdk5 and the ligand reelin has provided a conceptual framework for exploring the molecular mechanisms underlying proper lamination of the developing mammalian cerebral cortex. In this report, we identify a component of the regulation of Cdk5-mediated cortical lamination by genetic analysis of the roles of the class III POU Domain transcription factors, Brn-1 and Brn-2, expressed during the development of the forebrain and coexpressed in most layer II-V cortical neurons. Brn-1 and Brn-2 appear to critically control the initiation of radial migration, redundantly regulating the cell-autonomous expression of the p35 and p39 regulatory subunits of Cdk5 in migrating cortical neurons, withBrn-1(−/−)/Brn-2(−/−) mice exhibiting cortical inversion.
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POU Domain factors in the neuroendocrine system lessons from developmental biology provide insights into human disease
Endocrine Reviews, 2001Co-Authors: Bogi Andersen, Michael G RosenfeldAbstract:POU Domain factors are transcriptional regulators characterized by a highly conserved DNA-binding Domain referred to as the POU Domain. The structure of the POU Domain has been solved, facilitating the understanding of how these proteins bind to DNA and regulate transcription via complex protein-protein interactions. Several members of the POU Domain family have been implicated in the control of development and function of the neuroendocrine system. Such roles have been most clearly established for Pit-1, which is required for formation of somatotropes, lactotropes, and thyrotropes in the anterior pituitary gland, and for Brn-2, which is critical for formation of magnocellular and parvocellular neurons in the paraventricular and supraoptic nuclei of the hypothalamus. While genetic evidence is lacking, molecular biology experiments have implicated several other POU factors in the regulation of gene expression in the hypothalamus and pituitary gland. Pit-1 mutations in humans cause combined pituitary hormon...
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the role of POU Domain proteins in the regulation of mammalian pituitary and nervous system development
Progress in Nucleic Acid Research and Molecular Biology, 1999Co-Authors: Robert J. Mcevilly, Michael G RosenfeldAbstract:POU Domain proteins represent a subfamily of homeoDomain-containing transcription factors that are expressed in many animal orders in a number of distinct regions in the developing and adult organism. In mammals, the expression profiles of these factors have suggested roles for class I, class III, and class IV POU Domain proteins in the development, maintenance, and function of the endocrine and nervous systems. The genetic characterizations of the functions of these proteins during the generation, differentiation, and maturation of cells comprising these tissues have revealed a requirement for the individual actions of these transcription factors in the development of various elements of the anterior pituitary, the brain, and the somatosensory, vestibular/cochlear, and visual systems.
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characterization of skn 1a i POU Domain factors and linkage to papillomavirus gene expression
Journal of Biological Chemistry, 1997Co-Authors: Bogi Andersen, Ali Hariri, Mark R Pittelkow, Michael G RosenfeldAbstract:Abstract Tissue-restricted POU Domain transcription factors, which bind octamer or octamer-like gene sequences, play roles in cellular differentiation and the development of several organs. We have previously identified a POU Domain gene, Skn-1a/i, expressed primarily in epidermis, that encodes at least two products through alternative splicing. One of these, Skn-1a, acts as a transcriptional activator, and the other, Skn-1i, contains an inhibitory Domain in the NH2 terminus, which prevents DNA-binding in vitro and transcriptional activationin vivo. We now demonstrate that when Skn-1i is expressed in eukaryotic cells it can bind to an octamer site, suggesting thatin vivo cellular factors modulate the activity of the inhibitory Domain to permit DNA-binding. Yet the inhibitory Domain does not allow transactivation by Skn-1i or by a heterologous transactivator containing this Domain in cis. Furthermore, we demonstrate that Skn-1a, Tst-1, and Oct-1 are the major octamer-binding proteins in epidermis. Since Skn-1a is primarily expressed in suprabasal cells of the epidermis, we have tested its possible role in the regulation of epidermal papillomaviruses. In transient transfection assays, Skn-1a and Tst-1 can activate the long control region of the epidermis-specific human papillomavirus 1A (HPV-1A). Consistent with these in vivo transcription data, in vitro DNA binding studies identify three octamer-like sites, which are capable of binding Skn-1a, in the HPV-1A long control region. Mutations of all three octamer-like sites prevent transactivation by Skn-1a in transient transfection assays. Taken together, these results provide evidence that Skn-1a and Tst-1 may provide a molecular link between HPV gene expression and epidermal differentiation.
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Genetically defined roles of class I, class Iii, and class Iv POU Domain factors in the development of the mammalian endocrine and nervous systems
Current Opinion in Endocrinology & Diabetes, 1997Co-Authors: Robert J. Mcevilly, Michael G RosenfeldAbstract:Mammalian POU Domain proteins are expressed in diverse regions in the developing and adult organism. The patterns of expression suggest roles for class I, class III, and class IV POU Domain factors in the development of the neuroendocrine and nervous systems. Indeed, study of the activation, structure, and function of the class I factor, Pit-1, has revealed that it regulates terminal differentiation of three cell phenotypes by regulating classes of genes during anterior pituitary development. Similarly, insights into the roles of class III and class IV POU proteins, suggested through functional studies of class III and class IV protein DNA response elements, have been provided by analysis of genetic models in mice and humans. The consequences of the deletion or natural mutation of these genes are evaluated and compared with observations concerning potential actions of these factors in cell line models. Although the class III and class IV POU Domain transcription factors display early patterns of expression in the embryo, genetic evidence demonstrates that their roles are manifested relatively late in development, in the regulation of cell migration, phenotype, and survival.
Michael Wegner - One of the best experts on this subject based on the ideXlab platform.
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the class iii POU Domain protein brn 1 can fully replace the related oct 6 during schwann cell development and myelination
Molecular and Cellular Biology, 2005Co-Authors: Ralf P Friedrich, Beate Schlierf, Ernst R Tamm, Michael R Bosl, Michael WegnerAbstract:For differentiation, Schwann cells rely on the class III POU Domain transcription factor Oct-6, which is expressed transiently when Schwann cells have established a one-to-one relation with axons but have not yet started to myelinate. Loss of Oct-6 leads to a transient arrest in this promyelinating stage and a delay in myelination. Although the closely related POU Domain protein Brn-2 is coexpressed with Oct-6 in Schwann cells, its loss has only mild consequences. Combined loss of both POU Domain proteins, in contrast, dramatically increases the myelination delay, raising the question of how related POU Domain proteins compare to each other in their activities. Here, we have replaced Oct-6 expression in the mouse with expression of the class III POU Domain protein Brn-1. Although this protein is not normally expressed in Schwann cells, Brn-1 was capable of fully replacing Oct-6. Brn-1 efficiently induced Krox-20 expression as a prerequisite for myelination. Onset and extent of myelination were also indistinguishable from that of the wild type in mice that carried only Brn-1 instead of Oct-6 alleles. Similar to Oct-6, Brn-1 down-regulated its own expression at later stages of myelination. Thus, class III POU Domain proteins can fully replace each other in Schwann cell development.
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identification of the nuclear localization signal of the POU Domain protein tst 1 oct6
Journal of Biological Chemistry, 1996Co-Authors: Elisabeth Sock, Michael G Rosenfeld, Janna Enderich, Michael WegnerAbstract:Abstract POU Domain proteins are important regulators of development and terminal differentiation based upon their transcriptional activity in the nucleus. Here, we analyzed the mechanism underlying the nuclear localization of Tst-1/Oct6, a member of this family that regulates events during neurogenesis and myelination. Nuclear localization of Tst-1/Oct6 was dependent on the POU Domain, as its deletion prevented access to the nucleus, whereas its transfer to the amino terminus of β-galactosidase was sufficient to prompt nuclear accumulation of this normally cytosolic protein. Interestingly, nuclear localization and high affinity DNA binding were two independent functions of the POU Domain and could be separated in several mutants. While specific high affinity binding to DNA required the presence of both the POU-specific and the POU homeoDomain, the POU-specific Domain was dispensable for nuclear localization of Tst-1/Oct6. Rather, the nuclear localization function was selectively contained within the POU homeoDomain. Specifically, a basic cluster (GRKRKKRT) preceding helix 1 of the homeoDomain was shown by deletion mutagenesis to be involved in the nuclear localization of Tst-1/Oct6. This sequence, which is highly conserved among POU Domain proteins, was by itself capable of translocating β-galactosidase to the nucleus defining it as the bona fide nuclear localization signal of Tst-1/Oct6 and presumably other POU Domain factors.
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functional interaction between the POU Domain protein tst 1 oct 6 and the high mobility group protein hmg i y
Molecular and Cellular Biology, 1995Co-Authors: H Leger, Elisabeth Sock, K Renner, F Grummt, Michael WegnerAbstract:The POU Domain protein Tst-1/Oct-6 is a transcriptional activator of human papovavirus JC virus in transient transfections. Because of its endogenous expression in myelinating glia, Tst-1/Oct-6 might also be an important determinant for the glia specificity of JC virus in vivo. Activation of viral early and late genes depends on the ability of Tst-1/Oct-6 to interact with an AT-rich element within the viral regulatory region. Here, we show that this element not only is bound by Tst-1/Oct-6 but, in addition, serves as a binding site for the high-mobility-group protein HMG-I/Y. In the presence of HMG-I/Y, Tst-1/Oct-6 exhibited an increased affinity for this AT-rich element. The specificity of this effect was evident from the fact that no stimulation of Tst-1/Oct-6 binding was observed on a site that did not allow binding of HMG-I/Y. In addition, both proteins interacted with each other in solution. Direct contacts were identified between the POU Domain of Tst-1/Oct-6 and a short stretch of 10 amino acids in the central portion of HMG-I/Y. These results point to an accessory role for HMG-I/Y in the activation of JC viral gene expression by the POU Domain protein Tst-1/Oct-6. In agreement with such a role, HMG-Y synergistically supported the function of Tst-1/Oct-6 in transient transfections, measured on the early promoter of JC virus or on an artificial promoter consisting of only a TATA box and the common binding element for Tst-1 and HMG-I/Y.
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the POU Domain protein tst 1 and papovaviral large tumor antigen function synergistically to stimulate glia specific gene expression of jc virus
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: K Renner, H Leger, Michael WegnerAbstract:Abstract Synergism between transcriptional activators is a powerful way of potentiating their function. Here we show that the glial POU Domain protein Tst-1 (also known as Oct-6 and SCIP) and large tumor antigen (T antigen) synergistically increased transcription from both the early and the late promoters of papovavirus JC in glial cells. Synergism between both proteins did not require T-antigen-mediated DNA replication or direct binding of T antigen to the promoter. The ability of T antigen to functionally cooperate with Tst-1 was contained within its N-terminal region, shown by the fact that small tumor antigen (t antigen) could substitute for T antigen in transfection experiments. In addition to this functional synergism, a direct interaction between Tst-1 and T antigen was observed in vitro. Using deletion mutants of Tst-1 and T antigen, the POU Domain of Tst-1 and the N-terminal region of T antigen were found to participate in this interaction. Because of the low levels of Tst-1 present in oligodendrocytes, synergism between Tst-1 and T antigen could be an important factor in establishing the lytic infection of oligodendrocytes by JC virus during the course of the fatal demyelinating disease progressive multifocal leukoencephalopathy.
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POU Domain proteins structure and function of developmental regulators
Current Opinion in Cell Biology, 1993Co-Authors: Michael Wegner, Daniel W Drolet, Michael G RosenfeldAbstract:Abstract POU-Domain proteins are a group of developmental regulators found in organisms as distant as worm and man. The sequence conservation of the POU-Domain has allowed the characterization of increasing numbers of proteins containing the Domain, many of which act to control the generation and maintenance of differentiated cell phenotypes in organs as diverse as skin and brain. Analysis of the means by which POU-Domain proteins regulate transcription has led to a further understanding of how this group initiates specific developmental programs.
Bogi Andersen - One of the best experts on this subject based on the ideXlab platform.
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the POU Domain factor skin 1a represses the keratin 14 promoter independent of dna binding a possible role for interactions between skn 1a and creb binding protein p300
Journal of Biological Chemistry, 2001Co-Authors: Tod M Sugihara, Elena I Kudryavtseva, Vivek Kumar, Jackie J Horridge, Bogi AndersenAbstract:Abstract The genes encoding keratin 5 and 14 are highly expressed in the basal cell layer keratinocytes of the epidermis, but both genes are silenced when keratinocytes move into the suprabasal compartment. The POU homeoDomain factors Skn-1a and Tst-1, which are expressed in epidermis, may play a role in the suprabasal repression of the keratin 5 and 14 genes because keratin 14 mRNA expression persists in suprabasal cells in Skn-1/Tst-1 double knockout mice. In transfection experiments, both Skn-1a and Tst-1 repress the keratin 14 promoter, with the POU Domain being sufficient for repression. The region of the keratin 14 gene sufficient and required for repression by Skn-1a is a 100-base pair sequence lacking POU-binding sites adjacent to the transcription start site. DNA-binding defective mutants of Skn-1a and Tst-1 are as effective at mediating repression as the wild type proteins, suggesting that protein-protein interactions rather than direct DNA binding are important for repression. We also show that CREB-binding protein (CBP)/p300 co-activators are strong activators of keratin 14 gene expression, acting through sequences close to the keratin 14 promoter. Further, CBP interacts directly with the POU Domain of Skn-1a, and increasing concentrations of CBP can overcome Skn-1a-mediated repression, suggesting that POU Domain factors may repress keratin 14 gene expression by interfering with the activity of co-activators such as CBP/p300.
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POU Domain factors in the neuroendocrine system lessons from developmental biology provide insights into human disease
Endocrine Reviews, 2001Co-Authors: Bogi Andersen, Michael G RosenfeldAbstract:POU Domain factors are transcriptional regulators characterized by a highly conserved DNA-binding Domain referred to as the POU Domain. The structure of the POU Domain has been solved, facilitating the understanding of how these proteins bind to DNA and regulate transcription via complex protein-protein interactions. Several members of the POU Domain family have been implicated in the control of development and function of the neuroendocrine system. Such roles have been most clearly established for Pit-1, which is required for formation of somatotropes, lactotropes, and thyrotropes in the anterior pituitary gland, and for Brn-2, which is critical for formation of magnocellular and parvocellular neurons in the paraventricular and supraoptic nuclei of the hypothalamus. While genetic evidence is lacking, molecular biology experiments have implicated several other POU factors in the regulation of gene expression in the hypothalamus and pituitary gland. Pit-1 mutations in humans cause combined pituitary hormon...
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Functions of the POU Domain genes Skn-1a/i and Tst-1/Oct-6/SCIP in epidermal differentiation.
Genes & Development, 1997Co-Authors: Bogi Andersen, Robert J. Mcevilly, W C Weinberg, O Rennekampff, John R. Bermingham, Farideh Hooshmand, V Vasilyev, J F Hansbrough, M R Pittelkow, S H YuspaAbstract:Here we report on investigation of the role of the POU Domain genes Skin-1a/i (Skn-1a/i/Epoc/Oct-11) and Testes-1 (Tst-1/Oct-6/SCIP) in epidermis where proliferating basal keratinocytes withdraw from the cell cycle, migrate suprabasally, and terminally differentiate to form a multilayered, stratified epithelium. The expression of the Skn-1a/i and Tst-1 genes is linked to keratinocyte differentiation in vivo and in vitro, whereas the ubiquitous POU Domain factor Oct-1 is expressed highly in both proliferating and post-mitotic keratinocytes. Analysis of Skn-1a/i gene-deleted mice reveals that the Skn-1a/i gene modulates the pattern of expression of the terminal differentiation marker loricrin and inhibits expression of genes encoding markers of the epidermal keratinocyte wounding response. Although epidermis from Tst-1 gene-deleted mice develops normally, epidermis from mice deleted for both Skn-1a/i and Tst-1 is hyperplastic and fails to suppress expression of K14 and Spr-1 in suprabasal cells when transplanted onto athymic mice. This suggests that Skn-1a/i and Tst-1 serve redundant functions in epidermis. Therefore, at least two POU Domain genes, Skn-1a/i and Tst-1, serve both distinct and overlapping functions to regulate differentiation of epidermal keratinocytes during normal development and wound healing.
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characterization of skn 1a i POU Domain factors and linkage to papillomavirus gene expression
Journal of Biological Chemistry, 1997Co-Authors: Bogi Andersen, Ali Hariri, Mark R Pittelkow, Michael G RosenfeldAbstract:Abstract Tissue-restricted POU Domain transcription factors, which bind octamer or octamer-like gene sequences, play roles in cellular differentiation and the development of several organs. We have previously identified a POU Domain gene, Skn-1a/i, expressed primarily in epidermis, that encodes at least two products through alternative splicing. One of these, Skn-1a, acts as a transcriptional activator, and the other, Skn-1i, contains an inhibitory Domain in the NH2 terminus, which prevents DNA-binding in vitro and transcriptional activationin vivo. We now demonstrate that when Skn-1i is expressed in eukaryotic cells it can bind to an octamer site, suggesting thatin vivo cellular factors modulate the activity of the inhibitory Domain to permit DNA-binding. Yet the inhibitory Domain does not allow transactivation by Skn-1i or by a heterologous transactivator containing this Domain in cis. Furthermore, we demonstrate that Skn-1a, Tst-1, and Oct-1 are the major octamer-binding proteins in epidermis. Since Skn-1a is primarily expressed in suprabasal cells of the epidermis, we have tested its possible role in the regulation of epidermal papillomaviruses. In transient transfection assays, Skn-1a and Tst-1 can activate the long control region of the epidermis-specific human papillomavirus 1A (HPV-1A). Consistent with these in vivo transcription data, in vitro DNA binding studies identify three octamer-like sites, which are capable of binding Skn-1a, in the HPV-1A long control region. Mutations of all three octamer-like sites prevent transactivation by Skn-1a in transient transfection assays. Taken together, these results provide evidence that Skn-1a and Tst-1 may provide a molecular link between HPV gene expression and epidermal differentiation.
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POU Domain Transcription Factors in the Neuroendocrine System
Neural Cell Specification, 1995Co-Authors: Bogi Andersen, Linda Erkman, Peng Li, Robert J. Mcevilly, Marcus D. Schonemann, Eric E. Turner, Michael G RosenfeldAbstract:The precise molecular mechanisms by which distinct, mature neuronal phenotypes arise from a common primordium, in response to specific morphogens and signals, remains a fundamental question in neurobiology. We have discovered and characterized eight novel neuronally-expressed mammalian POU Domain transcription factors. Based on the distinct spatial and temporal patterns of their expression, and their structural similarity to critical determining factors in other organ systems, we hypothesize that these POU Domain factors exert essential roles in establishing specific neuronal and glial phenotypes and the patterns of connection between them. We have discovered the cognate DNA recognition elements for the three classes of neuronally-expressed POU Domain factors for Brn-1, Brn-2, Tst-1, Brn-4 (Class III), and Brn-3.0, Brn-3.1, and Brn-3.2 (Class IV), revealing differential spacing and orientation between the core elements of the bipartite DNA binding motif. Genetic methods are being used to critically test our hypothesis concerning the roles of these POU Domain factors in determining the generation and function of specific neuronal and glial phenotypes. Homologous recombination in embryonic stem cells will be used to generate mice null for these POU IV class genomic loci, alone and in combination. We plan to test the roles of these factors in differentiation and survival of sensory neurons in dorsal root ganglia, spinal cord, and retinal ganglion cells, and their connections. Furthermore, we plan to examine the role of the four Class III POU Domain factors, Brn-1, Brn-2, Tst-1 and Brn-3 in establishing central neuronal and glial phenotypes by gene deletion.
P C Van Der Vliet - One of the best experts on this subject based on the ideXlab platform.
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The Oct-1 POU Domain stimulates adenovirus DNA replication by a direct interaction between the viral precursor terminal protein-DNA polymerase complex and the POU homeoDomain.
The EMBO Journal, 1994Co-Authors: Frank E. J. Coenjaerts, J A W M Van Oosterhout, P C Van Der VlietAbstract:Abstract The bipartite POU Domain of transcription factor Oct-1 stimulates adenovirus DNA replication through an interaction with the octamer sequence present in the auxiliary origin. Employing an immobilized in vitro DNA replication system, we show that the POU Domain enhances the formation of a pre-initiation complex composed of the viral precursor terminal protein-DNA polymerase (pTP-pol) complex and the origin. To investigate the mechanism of stimulation we have explored protein-protein interactions between the POU Domain and the pTP-pol complex. Such an interaction could be detected using a GST-POU fusion protein bound to glutathione-agarose beads. Binding was also observed with the POU homeoDomain (POUHD), albeit weaker than with the intact POU Domain, but not with the POU specific subDomain. Four point mutations localized in the POUHD were analyzed for pTP-pol binding. Two of these, E22A and E30A, bound pTP-pol equally as well as the wild-type, while the other two, Q24A and E29A, were able to bind 2- to 4-fold better. These mutations are localized in the same region where the HSV transactivator VP16 binds, but did not coincide with the VP16 contacts. A direct correlation between pTP-pol binding and stimulation of DNA replication in vitro was observed for all mutants, suggesting that stimulation by the POU Domain is caused by an interaction with the viral pTP-pol complex.
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the dna binding specificity of the bipartite POU Domain and its subDomains
The EMBO Journal, 1992Co-Authors: C P Verrijzer, Marijke J. Strating, Mark J Alkema, W W Van Weperen, H C Van Leeuwen, P C Van Der VlietAbstract:Abstract The POU Domain is a conserved DNA binding region of approximately 160 amino acids present in a family of eukaryotic transcription factors that play regulatory roles in development. The POU Domain consists of two subDomains, the POU-specific (POUS) Domain and a POU-type homeoDomain (POUHD). We show here that, like the POUHD, the Oct-1 POUS Domain can bind autonomously to DNA but with low affinity. DNA binding studies and in vitro binding site selection revealed that the POU subDomains each have a different sequence specificity. The binding consensus of the POUS Domain [gAATAT(G/T)CA] and POUHD (RTAATNA) respectively overlap the 'left half' and right half' of the POU Domain recognition sequence [a(a/t)TATGC(A/T) AAT(t/a)t]. In addition to the core sequence, which is very similar to the octamer motif (ATGCAAAT), the flanking bases make a significant contribution to the binding affinity of the POU Domain. Interestingly, at some positions the sequence preferences of the isolated POU subDomains are distinct from those of the POU Domain, suggesting that the POU Domain binding site is more than a simple juxtaposition of the POUS and POUHD target sequences. In addition, analysis of the binding kinetics of the POU Domain and POUHD indicates that the POUS Domain enhances the binding affinity by reducing the dissociation rate. Our results show that the POU Domain proteins have DNA binding properties distinct from those of classic homeoDomain proteins. We suggest a model for the way in which an additional conserved Domain adds further specificity to DNA recognition by homeoDomain proteins.
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the oct 1 POU Domain mediates interactions between oct 1 and other POU proteins
Molecular and Cellular Biology, 1992Co-Authors: C P Verrijzer, J A W M Van Oosterhout, P C Van Der VlietAbstract:The POU Domain is the conserved DNA binding Domain of a family of gene regulatory proteins. It consists of a POU-specific Domain and a POU homeoDomain, connected by a variable linker region. Oct-1 is a ubiquitously expressed POU Domain transcription factor. It binds to the canonical octamer sequence (ATGCAAAT) as a monomer. Here we show by chemical cross-linking and protein affinity chromatography that the Oct-1 POU Domain monomers can interact in solution. This association requires both the POU homeoDomain and the POU-specific Domain. The interaction is transient in solution and can be stabilized by binding to the heptamer-octamer sequence in the immunoglobulin heavy-chain promoter. This correlates with cooperative DNA binding to this site. POU proteins from different subclasses, including Oct-1, Oct-2A, Oct-6, and a chimeric Oct-1 protein containing the Pit-1 POU Domain, can bind cooperatively to a double binding site and form a heteromeric complex.
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The DNA binding Domain (POU Domain) of transcription factor oct-1 suffices for stimulation of DNA replication.
The EMBO Journal, 1990Co-Authors: C P Verrijzer, P C Van Der VlietAbstract:Abstract Oct-1, also referred to as NFIII, OTF-1, OBP100 or NF-A1, is a ubiquitous sequence-specific DNA binding protein that activates transcription and adenovirus DNA replication. The protein contains a conserved DNA binding Domain (POU Domain) present in several transcription factors. We have overproduced oct-1, the related oct-2 and several oct-1 deletion mutants in a vaccinia expression system to identify the Domains important for activation of DNA replication in vitro. Both oct-1 and oct-2 stimulate adenovirus DNA replication in an octamer-dependent manner. From deletion studies it appears that the 160 amino acid long POU Domain suffices for stimulation. This Domain consists of two subDomains, a POU-specific and a homeo Domain. Deletion of the POU-specific Domain revealed that the homeo Domain has an intrinsic, but weak DNA binding activity and surprisingly, inhibits DNA replication. As the POU Domain does not coincide with the transcription activation Domain, these results indicate that, although oct-1 functions both in DNA replication and transcription, the mechanisms underlying these processes are probably distinct.
Jeremy Nathans - One of the best experts on this subject based on the ideXlab platform.
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POU Domain factor brn 3b is required for the development of a large set of retinal ganglion cells
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Mengqing Xiang, Lijuan Zhou, Daniel S Wagner, William H Klein, Jeremy NathansAbstract:Abstract The three members of the Brn-3 family of POU Domain transcription factors are found in highly restricted sets of central nervous system neurons. Within the retina, these factors are present only within subsets of ganglion cells. We show here that in the developing mouse retina, Brn-3b protein is first observed in presumptive ganglion cell precursors as they begin to migrate from the zone of dividing neuroblasts to the future ganglion cell layer, and that targeted disruption of the Brn-3b gene leads in the homozygous state to a selective loss of 70% of retinal ganglion cells. In Brn-3b (-/-) mice other neurons within the retina and brain are minimally or not at all affected. These experiments indicate that Brn-3b plays an essential role in the development of specific ganglion cell types.
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retina derived POU Domain factor 1 a complex POU Domain gene implicated in the development of retinal ganglion and amacrine cells
The Journal of Neuroscience, 1996Co-Authors: Hao Zhou, Takashi Yoshioka, Jeremy NathansAbstract:A novel POU-Domain protein, retina-derived POU-Domain factor-1 (RPF-1), has been identified through the isolation of cDNA and genomic DNA clones. In the adult, RPF-1 is expressed only within the CNS, where its expression is restricted to the medical habenulla, to a dispersed population of neurons in the dorsal hypothalamus, and to subsets of ganglion and amacrine cells in the retina. The human RPF-1 gene spans > 125 kb and gives rise to multiple differentially spliced transcripts. In the human retina, the most abundant mRNA isoforms are derived from an alternate splicing event that inserts an evolutionarily conserved peptide of 36 amino acids into the DNA recognition helix of the POU- specific Domain. In vitro, the RPF-1 POU Domain lacking the insert binds to a consensus Oct-1 binding site, whereas the alternately spliced POU Domain does not. RPF-1 protein first appears in the developing mouse retina at e11, where it localizes to neuroblasts that have recently migrated from the mitotic zone to the future ganglion cell layer. These data suggest that RPF-1 is likely to be involved in early steps in the differentiation of amacrine and ganglion cells.
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the brn 3 family of POU Domain factors primary structure binding specificity and expression in subsets of retinal ganglion cells and somatosensory neurons
The Journal of Neuroscience, 1995Co-Authors: Mengqing Xiang, Takashi Yoshioka, Lijuan Zhou, T B Shows, Jennifer P Macke, S H C Hendry, R L Eddy, Jeremy NathansAbstract:A search for POU Domain sequences expressed in the human retina has led to the identification of three closely related genes: Brn-3a, Brn-3b, and Brn-3c. The structure and expression pattern of Brn-3b was reported earlier (Xiang et al., 1993); we report here the structures and expression patterns of Brn-3a and Brn-3c. Antibodies specific for each Brn-3 protein were generated and shown to label only ganglion cells in a variety of vertebrate retinas. A complex pattern of strongly and weakly immunolabeled ganglion cells was observed in mouse, cat, and monkey retinae. In mouse and cat retinae, Brn-3a and Brn-3b proteins are found in a large fraction of ganglion cells, whereas Brn-3c is present in fewer ganglion cells. In the cat retina, anti-Brn-3a immunoreactivity was strong in the small ganglion cells (gamma cells) and weak in the remaining ganglion cells (alpha and beta cells); anti- Brn-3b immunoreactivity was present in all ganglion cells; and anti- Brn3c immunoreactivity was confined to the small ganglion cells. Immunolabeling of macaque retinae following retrograde labeling from the lateral geniculate nucleus revealed strong anti-Brn-3a immunoreactivity in a minority of retrogradely labeled P-type ganglion cells, and weak Brn-3a immunoreactivity in all of the remaining P- and M-type ganglion cells. In the same retinae, strong anti-Brn-3b immunoreactivity was seen in nearly all P-type ganglion cells and weak immunoreactivity in nearly all M-type ganglion cells. Each of the Brn-3- specific antibodies also labeled subsets of neurons in the dorsal root and trigeminal ganglia, suggesting that primary somatosensory neurons and retinal ganglion cells share genetic regulatory hierarchies. In vitro selection of an optimal DNA binding site using the Brn-3b POU Domain has revealed a consensus [(A/G)CTCATTAA(T/C)] that is recognized by each of the Brn-3 POU Domains and is distinct from binding sites previously described for other POU Domain proteins.
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brn 3b a POU Domain gene expressed in a subset of retinal ganglion cells
Neuron, 1993Co-Authors: Mengqing Xiang, Lijuan Zhou, Y W Peng, Roger L Eddy, T B Shows, Jeremy NathansAbstract:Abstract A search for POU Domain transcription factors in human retina cDNA has led to the identification of Brn-3b, a class IV POU Domain protein. Immunohistochemical experiments show that chicken, mouse, rabbit, monkey, and human retinas contain Brn-3b exclusively within a subpopulation of ganglion cells. In the adult mouse brain, Brn-3b is found only within cells in the deep layers of the superior colliculus, in the dorsal periaquaductal gray, and in a small cluster of cells in the brain stem near the area postrema. During the immediate postnatal period, cells containing Brn-3b are distributed in a number of regions within the brain stem and cerebellum. These data suggest that Brn-3b plays a role in determining and/or maintaining the identities of a small number of neurons, including a subset of visual system neurons.