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PubMed1998

Recruitment of octamer transcription factors to DNA by glucocorticoid receptor.

Glucocorticoid receptor (GR) and octamer transcription factors 1 and 2 (Oct-1/2) interact synergistically to activate the transcription of mouse mammary tumor virus and many cellular genes. Synergism correlates with cooperative DNA binding of the two factors in vitro. To examine the molecular basis for these cooperative interactions, we have studied the consequences of protein-protein binding between GR and Oct-1/2. We have determined that GR binds in solution to the octamer factor POU domain. Binding is mediated through an interface in the GR DNA binding domain that includes amino acids C500 and L501. In transfected mammalian cells, a transcriptionally inert wild-type but not an L501P GR peptide potentiated transcriptional activation by Oct-2 100-fold above the level that could be attained in the cell by expressing Oct-2 alone. Transcriptional activation correlated closely with a striking increase in the occupancy of octamer motifs adjacent to glucocorticoid response elements (GREs) on transiently transfected DNAs. Intriguingly, GR-Oct-1/2 binding was interrupted by the binding of GR to a GRE. We propose a model for transcriptional cooperativity in which GR-Oct-1/2 binding promotes an increase in the local concentration of octamer factors over glucocorticoid-responsive regulatory regions. These results reveal transcriptional cooperativity through a direct protein interaction between two sequence-specific transcription factors that is mediated in a way that is expected to restrict transcriptional effects to regulatory regions with DNA binding sites for both factors.

Animals↗
PubMed2005

Identification of cis-element regulating expression of the mouse Fgf10 gene during inner ear development.

Fibroblast growth factor (FGF) signaling is crucial for the induction and growth of the ear, a sensory organ that involves intimate tissue interactions. Here, we report the abnormality of Fgf10 null ear and the identification of a cis-regulatory element directing otic expression of Fgf10. In Fgf10 null inner ears, we found that the initial development of semicircular, vestibular, and cochlear divisions is roughly normal, after which there are abnormalities of semicircular canal/cristae and vestibular development. The mutant semicircular disks remain without canal formation by the perinatal stage. To elucidate regulation of the Fgf10 expression during inner ear development, we isolated a 6.6-kb fragment of its 5'-upstream region and examined its transcriptional activity with transgenic mice, using a lacZ-reporter system. From comparison of the mouse sequences of the 6.6-kb fragment with corresponding sequences of the human and chicken Fgf10, we identified a 0.4-kb enhancer sequence that drives Fgf10 expression in the developing inner ear. The enhancer sequences have motifs for many homeodomain-containing proteins (e.g., Prx, Hox, Nkx), in addition to POU-domain factors (e.g., Brn3), zinc-finger transcription factors (e.g., GATA-binding factors), TCF/LEF-1, and a SMAD-interacting protein. Thus, FGF10 signaling is dispensable for specification of otic compartment identity but is required for hollowing the semicircular disk. Furthermore, the analysis of a putative inner ear enhancer of Fgf10 has disclosed a complicated regulation of Fgf10 during inner ear development by numerous transcription factors and signaling pathways.

Animals↗
PubMed2005

The Optimedin gene is a downstream target of Pax6.

The Optimedin gene, also known as Olfactomedin 3, encodes an olfactomedin domain-containing protein. There are two major splice variants of the Optimedin mRNA, Optimedin A and Optimedin B, transcribed from different promoters. The expression pattern of the Optimedin A variant in the eye and brain overlaps with that for Pax6, which encodes a protein containing the paired and homeobox DNA-binding domains. The Pax6 gene plays a critical role for the development of eyes, central nervous system, and endocrine glands. The proximal promoter of the Optimedin A variant contains a putative Pax6 binding site in position -86/-70. Pax6 binds this site through the paired domain in vitro as judged by electrophoretic mobility shift assay. Mutations in this site eliminate Pax6 binding as well as stimulation of the Optimedin promoter activity by Pax6 in transfection experiments. Pax6 occupies the binding site in the proximal promoter in vivo as demonstrated by the chromatin immunoprecipitation assay. Altogether these results identify the Optimedin gene as a downstream target regulated by Pax6. Although the function of optimedin is still not clear, it is suggested to be involved in cell-cell adhesion and cell attachment to the extracellular matrix. Pax6 regulation of Optimedin in the eye and brain may directly affect multiple developmental processes, including cell migration and axon growth.

Alternative Splicing↗
PubMed2005

Identification of Pax2-regulated genes by expression profiling of the mid-hindbrain organizer region.

The paired domain transcription factor Pax2 is required for the formation of the isthmic organizer (IsO) at the midbrain-hindbrain boundary, where it initiates expression of the IsO signal Fgf8. To gain further insight into the role of Pax2 in mid-hindbrain patterning, we searched for novel Pax2-regulated genes by cDNA microarray analysis of FACS-sorted GFP+ mid-hindbrain cells from wild-type and Pax2-/- embryos carrying a Pax2(GFP) BAC transgene. Here, we report the identification of five genes that depend on Pax2 function for their expression in the mid-hindbrain boundary region. These genes code for the transcription factors En2 and Brn1 (Pou3f3), the intracellular signaling modifiers Sef and Tapp1, and the non-coding RNA Ncrms. The Brn1 gene was further identified as a direct target of Pax2, as two functional Pax2-binding sites in the promoter and in an upstream regulatory element of Brn1 were essential for lacZ transgene expression at the mid-hindbrain boundary. Moreover, ectopic expression of a dominant-negative Brn1 protein in chick embryos implicated Brn1 in Fgf8 gene regulation. Together, these data defined novel functions of Pax2 in the establishment of distinct transcriptional programs and in the control of intracellular signaling during mid-hindbrain development.

Animals↗
PubMed1997

The Pit-1 gene is regulated by distinct early and late pituitary-specific enhancers.

The differentiation of three anterior pituitary cell types is regulated by the tissue-specific POU domain factor Pit-1, which is initially expressed on Embryonic Day 13.5-14 in mice. The Pit-1 gene remains continuously, highly expressed in the somatotrope, thyrotrope, and lactotrope cells of the adult. Using the Pit-1-defective Snell dwarf as a genetic background, we demonstrate that the Pit-1 gene utilizes distinct enhancers for initial gene activation and for subsequent autoregulation (required for maintenance of expression) and that Pit-1-dependent activation of the distal enhancer can be mediated in the absence of the early enhancer. These two distinct enhancers provide the basis for temporally specific regulation by discrete pituitary-specific factors, events likely to be prototypic for regulation of other classes of genes encoding transcription factors controlling terminal differentiation.

Animals↗
PubMed2006

Xenopus Suppressor of Hairless 2 is involved in the cell fate decision during gastrulation through the transcriptional regulation of Xoct25/91.

We have previously indicated that Xenopus Suppressor of Hairless 2, XSu(H)2, is involved in the morphogenesis of gastrula embryos in a different manner from the XESR-1-mediated Notch signaling pathway. To address the downstream factors of XSu(H)2, we investigated the effect of XSu(H)2 on XenopusPOU-V genes, Xoct25 and Xoct91. Knockdown of XSu(H)2 caused the downregulation of Xoct25, Xoct91 and Xbrachyury. Dominant-negative Xoct25 caused the delay of blastopore closure with a decrease of Xbrachyury expression. Overexpression of Xoct25 or Xoct91 could rescue the decrease of Xbrachyury expression caused by XSu(H)2 depletion. XSu(H)2EnR inhibited Xoct25 and Xoct91 expressions in CHX-treated animal caps. Promoter analysis of the Xoct25 showed that the upstream region of Xoct25 contains the prospective Su(H) binding motif, which is essential for the transcription of Xoct25. These results suggest that XSu(H)2 is engaged in the cell fate decision during gastrulation through the gene expression of the Xoct25/91-mediated pathway.

Animals↗
PubMed2004

The role of Brn4/Pou3f4 and Pax6 in forming the pancreatic glucagon cell identity.

Brain 4 (Brn4/Pou3f4) and Pax6 are POU-homeodomain and paired-homeodomain transcription factors, respectively, that are expressed in the brain and the glucagon-expressing cells in the pancreas. Brn4 expression begins at embryonic day 10 in the pancreas, just before pax6 and both appear in the glucagon immunoreactive cells. At a later time point, E19, no Brn4 co-localization is observed with insulin or somatostatin but a rare pancreatic polypeptide (PP)-producing cell can be found, while Pax6 is found in all endocrine cells. These data suggest that brn4 is the only alpha-cell specific transcription factor yet identified; therefore, we sought to analyze alpha-cell development and function in mice with a targeted disruption of the brn4 gene. In homozygous brn4(-/-) mice, pancreatic bud formation, glucagon cell numbers and physiological measurements all appear normal. Examination of other transcription factors found in the glucagon cells showed normal Pax6 and Nkx2.2 immunoreactivity, suggesting that Brn4 does not regulate these transcription factors. Pax6 mutant mice (pax6(Sey/Sey)), with a natural inactivating mutation in pax6, have few endocrine cells but normal numbers of Brn4 and Nkx2.2 cells. The pancreatic phenotype of the pax6 mutants can be rescued with a YAC clone containing the human Pax6 gene.

Animals↗
PubMed1996

Transcription factors in disease.

Mutations affecting several predominantly tissue-specific transcriptional regulators have recently been associated with disease phenotypes. Although the mutational spectrum is variable, many of the reported cases involve clear loss-of-function mutations-such as Waardenburg syndrome type 1, aniridia and Rubinstein-Taybi syndrome-suggesting that the genetic mechanism involved in disease is haplo-insufficiency. The high degree of dosage sensitivity often appears to affect only a subset of the tissues that express the gene. Position effects with cytogenetic rearrangements well outside the coding region have been implicated for four of the genes discussed: POU3F4, SOX9, PAX6, and GL13.

Animals↗
PubMed1996

Identification of the nuclear localization signal of the POU domain protein Tst-1/Oct6.

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 beta-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 beta-galactosidase to the nucleus defining it as the bona fide nuclear localization signal of Tst-1/Oct6 and presumably other POU domain factors.

Amino Acid Sequence↗
PubMed2002

Brn-4 transcription factor expression targeted to the early developing mouse pancreas induces ectopic glucagon gene expression in insulin-producing beta cells.

The endocrine pancreas is comprised of beta and alpha cells producing the glucostatic hormones insulin and glucagon, respectively, and arises during development by the differentiation of stem/progenitor cells in the foregut programmed by the beta cell lineage-specific homeodomain protein Idx-1. Brain-4 (Brn-4) is expressed in the pancreatic anlaga of the mouse foregut at e10 in the alpha cells and transactivates glucagon gene expression. We expressed Brn-4 in pancreatic precursors or beta cell lineage in transgenic mice by placing it under either Idx-1 or insulin promoter (rat insulin II promoter) control, respectively. Idx-1 expression occurs at developmental day e8.5, and insulin expression occurs at e9.5, respectively. Misexpression of Brn-4 by the Idx-1 promoter results in ectopic expression of the proglucagon gene in insulin-expressing pancreatic beta cells, whereas misexpression by rat insulin II promoter did not. The early developmental expression of Brn-4 appears to be a dominant regulator of the glucagon expressing alpha cell lineage, even in the context of the beta cell lineage.

Animals↗
PubMed2005

Determination of transcription factors and their possible roles in the regulation of Pax3 gene expression in the mouse B16 F1 melanoma cell line.

The objective of this study was to determine which transcription factors regulate the expression of the Pax3 gene in the mouse B16 F1 melanoma cell line. The results showed that the -14 kilobase pair (kbp) Pax3 promoter, but not the -1.6 kbp Pax3 promoter, promoted Pax3 gene expression in B16 cells. Comparison of the sequence of the -14 kbp human Pax3 promoter with mouse Pax3 promoters indicated that homology sequences were located between -6.9 and -5.8 kbp, and also that the 1.1 kbp fragment (between -6.9 and -5.8 kbp), linked -1.6 kbp proximal to the Pax3 promoter [plasmid PGPax3PIV (N6.9/5.8) delta SST Lacz], could mimic the functions of plasmid PGPax3 -14(N-1.6) Lacz. Mutations of the core binding elements of either Pax3 site I or II or both sites I and II reduced significantly the beta-galactosidase (beta-gal) activity in the cells. However, mutations of the core binding sequences of site A or B increased significantly the beta-gal activity in the cells. Biochemistry analysis demonstrated that POU transcription factors (Oct-1 and Brn-2) bind to the specific binding elements of both sites I and II to stimulate Pax3 gene expression, whereas the TALE homeodomain-containing proteins (Pbx and Prep1) bind with the core binding sequences of sites A and B to repress the expression of the Pax3 gene in B16 cells.

Animals↗
PubMed1993

A tissue-specific enhancer confers Pit-1-dependent morphogen inducibility and autoregulation on the pit-1 gene.

Pit-1 is a tissue-specific POU domain factor obligatory for the appearance of three cell phenotypes in the anterior pituitary gland. Expression of the pit-1 gene requires the actions of a cell-specific 390-bp enhancer, located 10 kb 5' of the pit-1 transcription initiation site, within sequence that proves essential for effective pituitary targeting of transgene expression during murine development. The enhancer requires the concerted actions of a cell-specific cis-active element, Pit-1 autoregulatory sites, and atypical morphogen response elements. Pituitary ontogeny in the Pit-1-defective Snell dwarf mouse reveals that pit-1 autoregulation is not required for initial activation or continued expression during critical phases of Pit-1 target gene activation but, subsequently, is necessary for maintenance of pit-1 gene expression following birth. A potent 1,25-dihydroxyvitamin D3-responsive enhancer element defines a physiological site in which a single nucleotide alteration in the sequence of core binding motifs modulates the spacing rules for nuclear receptor response elements. Unexpectedly, the major retinoic acid response element is absolutely dependent on Pit-1 for retinoic acid receptor function. On this DNA element, Pit-1 appears to function as a coregulator of the retinoic acid receptor, suggesting an intriguing linkage between a cell-specific transcription factor and the actions of morphogen receptors that is likely to be prototypic of mechanisms by which other cell-specific transcription factors might confer morphogen receptor responsivity during mammalian organogenesis.

Animals↗
PubMed1995

Pit-1 binding to specific DNA sites as a monomer or dimer determines gene-specific use of a tyrosine-dependent synergy domain.

Transcriptional activation of the prolactin and growth hormone genes, occurring in a cell-specific fashion, requires short-range synergistic interactions between the pituitary-specific POU domain factor Pit-1 and other transcription factors, particularly nuclear receptors. Unexpectedly, we find that these events involve the gene-specific use of alternative Pit-1 synergy domains. Synergistic activation of the prolactin gene by Pit-1 and the estrogen receptor requires a Pit-1 amino-terminal 25-amino-acid domain that is not required for analogous synergistic activation of the growth hormone promoter. The action of this Pit-1 synergy domain is dependent on the presence of two of three tyrosine residues spaced by 6 amino acids and can be replaced by a comparable tyrosine-dependent trans-activation domain of an unrelated transcription factor (hLEF). The gene-specific utilization of this tyrosine-dependent synergy domain is conferred by specific Pit-1 DNA-binding sites that determine whether Pit-1 binds as a monomer or a dimer. Thus, the critical DNA site in the prolactin enhancer, where this domain is required, binds Pit-1 as a monomer, whereas the Pit-1 sites in the growth hormone gene, which do not utilize this synergy domain, bind Pit-1 as a dimer. The finding that the sequence of specific DNA sites dictates alternative Pit-1 synergy domain utilization based on monomeric or dimeric binding suggests an additional regulatory strategy for differential target gene activation in distinct cell types.

Amino Acid Sequence↗
PubMed1996

Interdependent transcription control elements regulate the expression of the SPRR2A gene during keratinocyte terminal differentiation.

Expression of the SPRR2A gene, a member of the small proline-rich family of cornified cell envelope precursor proteins, is strictly linked to keratinocyte terminal differentiation both in vivo and in vitro. In this study, we explored the molecular mechanisms underlying this regulation in transiently transfected primary keratinocytes induced to differentiate in vitro. Deletion mapping and site-directed mutagenesis of SPRR2A promoter-chloramphenicol acetyltransferase constructs indicate that four transcription control elements are essential and sufficient for promoter activity. These elements were further characterized by electrophoretic mobility shift and identified as (i) an inverted octamer doublet, bound by the POU domain factor Oct-11 (Skn-1a/i, Epoc-1), (ii) an interferon-stimulated response element recognized by interferon regulatory factors 1 and 2, (iii) an Ets binding site partially overlapping the interferon-stimulated response element, and (iv) a TG box recognized by the Sp1 family of zinc finger transcription factors. Destruction of a single terminal differentiation element is sufficient to completely abolish transcription from the SPRR2A promoter, indicating that these transcription control elements function in concert in an interdependent manner. Apparently, integration of signals transmitted by the above-mentioned transcription factors is necessary and sufficient to promote gene expression during keratinocyte terminal differentiation.

Base Sequence↗
PubMed1996

Molecular biology of pituitary development and disease.

The major endocrine cell types of the anterior and intermediate pituitary arise in sequential order during development. Our laboratory seeks to understand the molecular basis for different lineages among these cell types. Previous data from our group and others have shown that the POU-domain factor, Pit-1, and the orphan nuclear receptor, SF-1, are critical in the specification and maintenance of these cell types. The analysis of naturally occurring mutations revealed that Pit-1 is needed for development of three cell types, the thyrotropes (thyroid-stimulating hormone), somatotropes (growth hormone), and lactotropes (prolactin). Recently, a genetically engineered mouse mutant demonstrated that SF-1 is required for the maintenance of the gonadotrope (luteinizing hormone/follicle-stimulating hormone) cellular phenotype. To date, a similar factor for the corticotrope and melanotrope lineages expressing propiomelanocortin (POMC) has not been identified. Surprisingly, the serotonin (5-HT) neurotransmitter receptor 5-HT3 was found to be expressed in the anterior and intermediate lobes of the developing rodent pituitary. We are using this new marker to examine the molecular basis of the POMC lineages.

Animals↗
PubMed2000

The role of Otx and Otp genes in brain development.

Over the last ten years, many genes involved in the induction, specification and regionalization of the brain have been identified and characterized at the functional level through a series of animal models. Among these genes, both Otx1 and Otx2, two murine homologues of the Drosophila orthodenticle (otd) gene which encode transcription factors, play a pivotal role in the morphogenesis of the rostral brain. Classical knock-out studies have revealed that Otx2 is fundamental for the early specification and subsequent maintenance of the anterior neural plate, whereas Otx1 is mainly necessary for both normal corticogenesis and sense organ development. A minimal threshold of both gene products is required for correct patterning of the fore-midbrain and positioning of the isthmic organizer. A third gene, Orthopedia (Otp) is a key element of the genetic pathway controlling development of the neuroendocrine hypothalamus. This review deals with a comprehensive analysis of the Otx1, Otx2 and Otp functions, and with the possible evolutionary implications suggested by the models in which the Otx genes are reciprocally replaced or substituted by the Drosophila homologue, otd.

Animals↗
PubMed2003

The POU proteins Brn-2 and Oct-6 share important functions in Schwann cell development.

The genetic hierarchy that controls myelination of peripheral nerves by Schwann cells includes the POU domain Oct-6/Scip/Tst-1and the zinc-finger Krox-20/Egr2 transcription factors. These pivotal transcription factors act to control the onset of myelination during development and tissue regeneration in adults following damage. In this report we demonstrate the involvement of a third transcription factor, the POU domain factor Brn-2. We show that Schwann cells express Brn-2 in a developmental profile similar to that of Oct-6 and that Brn-2 gene activation does not depend on Oct-6. Overexpression of Brn-2 in Oct-6-deficient Schwann cells, under control of the Oct-6 Schwann cell enhancer (SCE), results in partial rescue of the developmental delay phenotype, whereas compound disruption of both Brn-2 and Oct-6 results in a much more severe phenotype. Together these data strongly indicate that Brn-2 function largely overlaps with that of Oct-6 in driving the transition from promyelinating to myelinating Schwann cells.

Animals↗