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PubMed1998

Transcriptional activation of the mouse peripherin gene by leukemia inhibitory factor: involvement of STAT proteins.

Peripherin is a neuron-specific intermediate filament protein whose expression is activated in vitro by the neuropoietic cytokines leukemia inhibitory factor (LIF) and interleukin-6. We have studied the mechanisms of transcriptional activation of the peripherin gene by LIF. In particular, we have identified a 70-bp element [peripherin cytokine-responsive element (Pe-CyRE)] within the 5'-flanking sequences of the mouse peripherin gene (between -930 and -860) that enhances transcription in two neuroblastoma cell lines, NBFL and LA-N-2, in response to LIF treatment. We have also shown by DNA mobility shift assays that treatment of cells by LIF induces the binding of protein complexes composed of at least two members of the signal transducers and activators of transcription (STAT) factor family to a cis element (Pe-APRE2) within Pe-CyRE. Furthermore, the entire Pe-CyRE, as well as Pe-APRE2, conferred responsiveness onto a heterologous thymidine kinase promoter. However, the response amplitude of the heterologous promoter to LIF was lower than that observed with the 5'-flanking sequences of the peripherin promoter, suggesting that cooperative interactions with surrounding sequences of the peripherin gene are required for a full transcriptional activation.

Acute-Phase Proteins↗
PubMed1991

Network antibodies identify nuclear lamin B as a physiological attachment site for peripherin intermediate filaments.

We studied the molecular associations between peripherin (a neuronal, type III intermediate filament subunit) and nuclear lamins. We show here that isolated peripherin binds selectively to mammalian lamin B under in vitro conditions. We further demonstrate that a synthetic peptide, representing the proximal part of peripherin's tail domain (P1), also associates with mammalian lamin B in a saturable, cooperative, and specific fashion. Laboratory animals immunized with P1 spontaneously develop idiotypic and anti-idiotypic antibodies recognizing peripherin and lamin B, respectively. These data provide essentially in vivo evidence that lamin B represents a constitutive nuclear "receptor" site for the tail domains of peripherin intermediate filaments.

Amino Acid Sequence↗
PubMed2004

Expression of peripherin in ubiquinated inclusions of amyotrophic lateral sclerosis.

We evaluated the expression of the type III intermediate filament (IF) protein, peripherin (PRP), in ubiquinated inclusions of motor neurons in amyotrophic lateral sclerosis (ALS). A previous study showed that overexpression of PRP in transgenic mice induces motor neuron disease with formation of PRP-containing inclusions before onset of symptoms [J. Cell Biol. 147 (3) (1999) 531]. To determine whether PRP inclusions occur in the human disease, we applied doublelabeling immunofluorescence to paraffin sections of the spinal cord obtained by autopsy of 40 ALS patients with sporadic disease and 39 controls. Inclusions that expressed immunoreactive ubiquitin and peripherin were recorded by video camera, and the sections were stained by hematoxylin and eosin (H&E) to define morphology. Lewy body-like inclusions (LBLIs) were seen in motor neuron perikarya of 9 of 40 ALS cases and none in controls; all LBLIs expressed peripherin. Skein-like inclusions (SLIs) were identified by ubiquitin, but did not express PRP with rare exceptions. Neither skein-like inclusions nor LBLIs expressed alpha B-crystallin, neurofilament protein (NF-L, NF-M and NF-H subunits), alpha-internexin, actin or alpha-synuclein. Immunoblot of the whole spinal cord exhibited a single 57-kDa band of peripherin in ALS patients and controls. Our data document the expression of peripherin in LBLIs, which may provide a clue to the pathogenesis of neurodegeneration in ALS.

Adult↗
PubMed2002

Murine peripherin gene sequences direct Cre recombinase expression to peripheral neurons in transgenic mice.

Spatially and temporally regulated somatic mutations can be achieved by using the Cre/loxP recombination system of bacteriophage P1. To develop a cell type-specific system of gene targeting in the peripheral nervous system, we generated the transgenic mouse lines expressing Cre recombinase under the control of the mouse peripherin gene promoter. The activity of the Cre recombinase during embryonic development was examined by mating the peripherin-Cre transgenic mice to the knock-in Cre-mediated recombination reporter strain, R26R. Analysis of F1 embryos from this cross showed specific excision of loxP-flanked sequences in the dorsal root ganglia, trigeminal ganglia, and olfactory epithelium, in a pattern very similar to the expression of the endogenous mouse peripherin gene, and the previously reported peripherin-lacZ transgenic mice. Thus, the peripherin-Cre mouse described here will provide a valuable tool for Cre-loxP-mediated conditional expression in the peripheral nervous system.

Animals↗
PubMed1996

Activity of the distal positive element of the peripherin gene is dependent on proteins binding to an Ets-like recognition site and a novel inverted repeat site.

The peripherin gene, encoding a neuron-specific intermediate filament protein, is transcriptionally induced when PC12 cells begin to terminally differentiate into neurons in response to nerve growth factor. Previously we identified two regulatory sequences of the peripherin gene: a proximal negative element (centered at -173), which prevents peripherin expression in undifferentiated PC12 cells, and a distal positive region (-2660 to -2308) necessary for full induction of peripherin in differentiated PC12 cells (Thompson, M., Lee, E. Lawe, D., Gizang-Ginsberg, E., and Ziff, E. (1992) Mol. Cell. Biol. 12,2501-2513). Here we define a distal positive element (DPE, -2445 to -2337) within the distal positive region. Methylation interference footprinting of the DPE identified DNA-protein contact points at a novel inverted repeat sequence (AACCACTGGTT) and an Ets-like recognition sequence (CAGGAG). Functional analysis using site-directed mutagenesis demonstrates that both sites are necessary for the activity of the DPE. In addition, ternary complex formation at the DPE is dependent on both sites. Antibody competition assays confirm that an Ets family member participates in the DNA-protein complex. We have indirect evidence that the inverted repeat binding protein and the Ets-related protein interact directly with each other. Finally, we demonstrate that the DPE is constitutively active and that neuron-specific regulation of peripherin expression may be due to interaction with distal and proximal negative regulatory elements.

Animals↗
PubMed2002

Murine model of autosomal dominant retinitis pigmentosa generated by targeted deletion at codon 307 of the rds-peripherin gene.

We introduced a targeted single base deletion at codon 307 of the rds-peripherin gene in mice, similar mutations being known to cause autosomal dominant retinitis pigmentosa (RP) in man. Histopathological and electroretinographic analysis indicate that the retinopathy in mice homozygous for the codon 307 mutation appears more rapid than that in the naturally occurring null mutant, the rds(-/-) mouse, suggesting that the rds-307 mutation displays a dominant negative phenotype in combination with that due to haplosufficiency. RP is the most prevalent cause of registered visual handicap in those of working age in developed countries, the 50 or so mutations so far identified within the RDS-peripherin gene accounting for up to 10% of dominant cases of the disease. Given the sequence homologies that exist between the murine rds-peripherin and the human RDS-peripherin gene, this disease model, the first to be generated for peripherin-based RP using gene targeting techniques, should in principle be of value in the work-up in mice of therapeutics capable of targeting transcripts derived from the human gene.

Amino Acid Sequence↗
PubMed1992

Nerve growth factor-induced derepression of peripherin gene expression is associated with alterations in proteins binding to a negative regulatory element.

The peripherin gene, which encodes a neuronal-specific intermediate filament protein, is transcriptionally induced with a late time course when nerve growth factor (NGF) stimulates PC12 cells to differentiate into neurons. We have studied its transcriptional regulation in order to better understand the neuronal-specific end steps of the signal transduction pathway of NGF. By 5' deletion mapping of the peripherin promoter, we have localized two positive regulatory elements necessary for full induction by NGF: a distal positive element and a proximal constitutive element within 111 bp of the transcriptional start site. In addition, there is a negative regulatory element (NRE; -179 to -111), the deletion of which results in elevated basal expression of the gene. Methylation interference footprinting of the NRE defined a unique sequence, GGCAGGGCGCC, as the binding site for proteins present in nuclear extracts from both undifferentiated and differentiated PC12 cells. However, DNA mobility shift assays using an oligonucleotide probe containing the footprinted sequence demonstrate a prominent retarded complex in extracts from undifferentiated PC12 cells which migrates with slower mobility than do the complexes produced by using differentiated PC12 cell extract. Transfection experiments using peripherin-chloramphenicol acetyltransferase constructs in which the footprinted sequence has been mutated confirm that the NRE has a functional, though not exclusive, role in repressing peripherin expression in undifferentiated and nonneuronal cells. We propose a two-step model of activation of peripherin by NGF in which dissociation of a repressor from the protein complex at the NRE, coupled with a positive signal from the distal positive element, results in depression of the gene.

Animals↗
PubMed1999

Involvement of intronic sequences in cell-specific expression of the peripherin gene.

Peripherin is an intermediate filament protein expressed in restricted populations of neurons. Our previous study of the chromatin structure of the mouse peripherin gene in cells that do or do not express peripherin suggested that the region located between -1,500 and +800 bp of the gene could be involved in its cell specificity. In the present work, we performed an in vitro functional analysis of the 5' flanking region of the mouse peripherin gene and observed that this region up to 9 kb contained both enhancer and inhibiting activities; however, it was insufficient to achieve a complete extinction of reporter gene expression in peripherin-negative cells. Furthermore, analysis of the first three introns with the 5' flanking sequences of the gene showed that intron I greatly increased specificity of the gene expression. Intron I also conferred the same properties to thymidine kinase heterologous promoter. DNase I footprinting experiments performed with intron I revealed at least two protected regions (Inl A and Inl B). Inl A encompasses an AP-2-like binding site that interacted with both neuroblast and fibroblast nuclear factors, as well as with the recombinant AP-2alpha protein. However, gel shift experiments suggested that the interacting nuclear factors are distinct from AP-2alpha itself and probably belong to the AP-2 family. Inl B perfectly matched the consensus binding site for Sp1 and specifically interacted with nuclear protein factors that showed the same binding properties as the Sp1 family members. Fine deletion analysis of intron I indicated that the Inl A element alone is responsible for its enhancing properties, whereas a region located between +789 and +832 gives to intron I its silencer activity.

3T3 Cells↗
PubMed2004

[Genetic analysis of rhodopsin and peripherin genes in patients with autosomal dominant retinitis pigmentosa (adRP) in Polish families].

PURPOSE: The aim of that study was to identify the mutations in rhodopsin and peripherin genes in Polish families with autosomal dominant form of retinitis pigmentosa and determine the population polymorphism in both genes in adRP families. MATERIAL AND METHODS: We performed ERG, visual acuity, Goldman visual fields, intraocular pressure measurements and fundoscopy in all the patients included in the study. On the basis of disease history, the families pedigree was made and the mode of inheritance was analyzed. The molecular analysis of DNA for each family with adRP was conducted. Genomic DNA was obtained from leucocytes by phenol-chloroform procedure according to Maniatis protocol. DNA was amplified by the PCR reaction in a volume of 50 microl containing 100 ng/microl of genomic DNA, water, Cetus buffer pH 8.4 (1 n Tris, 1 n MgCl, 1 n KCl, 2% gelatin), 0.25 microM of each primer, 200 microM of each of dATP, dTTP, dCTP, and dGTP and 2.5 U Taq polymerase (Promega). For amplification of rhodopsin gene 30 cycles of PCR were carried out. Each cycle consisting of denaturation at 95 degrees C for 5 min, annealing: at 58 degrees C (exon 1), 63 degrees C (exon 2 and 3), 68 degrees C (exon 4) and 2 min extension at 72 degrees C min. For amplification of peripherin gene 30 cycles of PCR were carried out with annealing at 60 degrees C. The entire PCR product was in electrophoresis on 8% PAA. The PCR-RFLP PCR-HD PCR-SSCP and analysis of polymorphism (CA)n dinucleotide repetition was performed. RESULTS: Molecular study demonstrated, that mutations in rhodopsin gene were cause of retinitis pigmentosa in case of two families. In any study families mutations in peripherin gene were not identified. Two kinds of bases polymorphism were identified: restriction fragments length polymorphism (RFLP) in rhodopsin gene in exon 1 and 3 and single strand conformation polymorphism (SSCP) in exon 1 and 3 in rhodopsin gene and in exon 3 in peripherin gene. The confirmed mutations in rhodopsin gene, cosegregation with adRP, whereas two kinds of population polymorphism did not correlate with clinical symptoms. Natural polymorphism appeared to be a frequent feature in rhodopsin gene while a less frequent feature in peripherin gene. CONCLUSIONS: Genetic investigations in patients with adRP allow to confirm the diagnosis and evaluate the prognosis. The mutation in rhodopsin gene should be confirmed in directly sequencing reaction in next study.

DNA Mutational Analysis↗
PubMed1993

Peripherin, a neuronal intermediate protein, is stably expressed by neuroendocrine carcinomas of the skin, their xenograft on nude mice, and the corresponding primary cultures.

The histogenesis of neuroendocrine carcinomas of the skin is still controversial. To determine the degree of neural differentiation of these neoplasias, we studied the expression of intermediate filament proteins in tumoral tissues. Expressions of peripherin, the neurofilament protein NF-L, vimentin, and cytokeratin 8 were analyzed by immunohistochemical methods on 12 human primary tumors and 3 tumor xenografts on nude mice. Peripherin was detected in 10 primary tumors by immunofluorescence. The protein and the corresponding messenger RNA were identified by two-dimensional gel electrophoresis and Northern analysis in extracts of an immunofluorescence-negative tumor. Peripherin, NF-L, and cytokeratin 8 were detected in tumoral cells, whereas vimentin was found exclusively in the stroma. The histological and ultrastructural properties of the original cells of neuroendocrine carcinomas of the skin, as well as coexpression of peripherin, cytokeratin 8, and neurofilament polypeptides, were preserved in tumor xenografts and their primary cultures in vitro. These results bring new elements to the knowledge of the biology of neuroendocrine carcinomas of the skin and indicate that peripherin constitutes a marker for tumor identification.

Animals↗
PubMed1993

Intragenic sequences are required for cell type-specific and injury-induced expression of the rat peripherin gene.

Peripherin is a 57 kDa type III intermediate-filament protein that is thought to play a role in axonogenesis both during development and following nerve injury (Oblinger et al., 1989; Escurat et al., 1990; Gorham et al., 1990; Troy et al., 1990b). We have used transgenic mouse technology to define peripherin gene sequences that are necessary for cell type-specific expression and for the increase in peripherin that occurs in response to axonal injury. Correct temporal and nervous system-specific expression resulted when 5.8 kilobases of peripherin 5' flanking sequence were linked to a reporter gene, but precise cell type-specific expression was achieved only when intragenic sequences were included. When intragenic sequences were present, peripherin transgenes were expressed in dorsal root ganglion neurons and spinal cord motor neurons and were upregulated in these cells following nerve injury.

Amino Acid Sequence↗
PubMedDate not supplied

Expression of the intermediate filament peripherin in skin tumors.

Peripherin is a neuronal intermediate filament reportedly expressed in neuroendocrine skin carcinomas and some melanocytic tumors. In order to assess the diagnostic usefulness of antibodies to peripherin in dermatopathology, we studied its expression in 68 skin tumors mostly of neural origin, and compared this expression with that of neurofilaments, a well-established neuronal marker. Antibodies to peripherin and neurofilaments both labeled dermal neurons present in normal skin and within the tumors. Specific labeling of tumor cells for peripherin was seen in only 2/5 neuroendocrine skin carcinomas, 3/18 benign nevi and 7/19 melanomas; even in these cases the percentage of tumor cells did not exceed 20%. We conclude that antibodies to peripherin may be used for the demonstration of cutaneous neurons in normal and diseased skin; however their diagnostic usefulness appears limited, less than that of antibodies to neurofilaments.

Humans↗
PubMed1994

LHRH cells migrate on peripherin fibers in embryonic olfactory explant cultures: an in vitro model for neurophilic neuronal migration.

Luteinizing hormone releasing hormone (LHRH) neurons arise from progenitor cells in the olfactory placode. During prenatal development, these cells migrate via neurophilic interactions, in track-like arrangements along axons of the olfactory complex. The mechanisms by which these cells attain an adult-like distribution are unknown. In this study, we established an in vitro, embryonic mouse olfactory explant model to examine the factors directing LHRH cell migration. Cultures were generated from E11.5 embryos and maintained for up to 3 weeks. Typically 20-50% (160-400 LHRH cells) of the total LHRH neuronal population survived and maintained gene expression in these explants. Fibronectin and laminin staining delineated substratum producing cells which concentrically spread, from Days 1-7, from the periphery of the entire explanted tissue. In contrast, LHRH cells emigrated exclusively from inside olfactory pit areas to the surface of the culture after 3 days. The relationship between groups of LHRH cells emerging from bilateral olfactory pits was not random, but highly organized; in 93% of the cultures examined, the angular relationship between these groups was 180-270 degrees. After 5 or more days in vitro, LHRH cells were found in directional tracks similar to those observed in vivo forming a continuum from the olfactory pit out onto the substratum, where many bipolar LHRH cells were discretely located. The maximum distance away from the olfactory pit that LHRH cells were detected was 0.9 mm, which is compatible with the distance traversed by LHRH cells through the nasal region in vivo. The reproducible spatiotemporal appearance of LHRH cells was unrelated to the concentric spread of the fibronectin and laminin producing cells of the explant. Taken together, these data indicate that LHRH cells migrated directionally in these explants and that the molecular cues governing the initial migration of these neurons remained intact in this system in the absence of brain tissue. Double-label immunocytochemistry indicated that at least three populations of neuronal fibers existed in the explants: N-CAM-positive, peripherin-positive, and N-CAM/peripherin-positive. Although all three fibers groups showed highly organized spatiotemporal distribution patterns, only peripherin-positive fibers correlated with the location of LHRH cells. LHRH cells were always preceded by, and in close association with, peripherin-positive fibers. We hypothesize that signals arising from the peripherin-positive axons provide the appropriate guidance cues to LHRH cells as they emigrate from the olfactory pit.

Animals↗
PubMed1994

A subset of peripherin positive olfactory axons delineates the luteinizing hormone releasing hormone neuronal migratory pathway in developing mouse.

Luteinizing hormone releasing hormone (LHRH) neurons in the CNS are derived from cells of the olfactory placode and thereafter migrate from the olfactory pit into the diencephalon. In this study, we examined embryonic LHRH neurons and the LHRH migratory pathway for several markers. During development, N-CAM and peripherin mRNA were expressed by olfactory epithelia, but not by LHRH cells. In nasal regions, olfactory axons were not immunostained by laminin or fibronectin antibodies, but were robustly peripherin and N-CAM immunoreactive. Although the majority of these axonal tracks entered the developing olfactory bulbs, a small population of peripherin positive but N-CAM negative axons turned caudally into the developing forebrain. LHRH cells were consistently juxtaposed to these axons. We propose that this peripherin positive/N-CAM negative fiber track is the anatomical pathway upon which LHRH cells migrate from the olfactory pit into the diencephalon.

Animals↗
PubMed1995

Peripherin gene is linked to keratin 18 gene on human chromosome 12.

Peripherin is a neuron-specific intermediate filament (IF) protein, found primarily in phylogenetically old regions of the nervous system. Whereas other neuronal IF genes have only two to three introns and are scattered in the genome, the peripherin gene (PRPH) has a complex intron-exon structure like nonneuronal IF genes that are clustered in tandem arrays, e.g., those encoding the keratins. We used a cosmid containing the human peripherin gene (PRPH) to determine its chromosomal location in relationship to nonneuronal IF genes. Using a rodent-human mapping panel, we localized the PRPH gene to human chromosome 12. Since a cluster of keratin genes maps to 12q12-13, polymorphic markers were developed for PRPH and for one of the keratin genes presumed to be in the cluster, keratin 18 (KRT18). Both markers were typed in CEPH reference families. Pairwise and multipoint analyses of the CEPH data revealed that KRT18 is tightly linked to DNA markers D12S4, D12S22, D12S90, D12S96 and D12S103, which lie between D12S18 and D12S8, with odds greater than 1000:1. These markers are physically located at 12q11-13, thus supporting the fine localization of KRT18 in or near the group of type II keratins in this region. Furthermore, linkage analysis showed that the peripherin gene (PRPH) is tightly linked to KRT18 (Z = 15.73, theta = 0.013), and therefore appears to be in close proximity to the cluster.

Base Sequence↗
PubMed1989

Phosphorylation of peripherin, an intermediate filament protein, in mouse neuroblastoma NIE 115 cell line and in sympathetic neurons.

Peripherin, an intermediate filament protein, described recently, is expressed in well defined neuronal populations. We studied the phosphorylation, in vivo, of this protein in mouse neuroblastoma NIE 115 cell line and in sympathetic neurons labelled with [32P]-orthophosphate. The autoradiograms of proteins separated on two-dimensional polyacrylamide gels were compared with the Coomassie-blue stainings. The results show that peripherin occurs as a mixture of phosphorylated and non-phosphorylated isoforms, and that these forms coexist in both differentiated and non-differentiated cells. We demonstrate by cleavage at the unique tryptophan residue, a characteristic shared by most other intermediate filament proteins (IFP), that the phosphorylation sites are located on the amino-terminal half of peripherin as it is for vimentin and desmin. These results are discussed in relation to the organization of the filamentous network constituted by peripherin.

Animals↗
PubMed1991

The peripherin gene maps to mouse chromosome 15.

We have mapped the mouse peripherin gene, Prph, to chromosome 15 by means of Southern analysis of a panel of Chinese hamster/mouse somatic cell hybrids using a rat peripherin cDNA probe. Peripherin is a recently characterized type III intermediate filament expressed in the peripheral and the central nervous system. Although its exact function is not known, peripherin is likely to be involved in the neuronal cytoskeleton, a role it shares with other intermediate filaments, such as the neurofilament proteins. The intermediate filament gene family is believed to have evolved via gene duplication and dispersal throughout the genome; these processes have resulted in clusters of intermediate filament genes on specific chromosomes and conservation of these chromosomal locations among mammalian species.

Animals↗
PubMed2000

Mouse peripherin isoforms.

Three distinct mRNAs have been shown to be produced by alternative splicing from the unique mouse peripherin gene. They generate three translation products, one major form, Pe-58, and two minor forms, Pe-56 which possess a shorter C-terminal sequence, and Pe-61 in which an additional sequence has been inserted in the central rod domain (Landon et al., 1989, EMBO J. 8, 1719-1726). In this study, the simultaneous occurrence of multiple transcripts in murine nervous tissues and neuroblastoma cell lines was shown by PCR amplification of fragments overlapping the sites of alternative splicing. Recombinant peripherin isoforms were purified from E. coli expressing full-length cDNAs. Rabbit antisera were raised against synthetic peptides mimicking parts of the two C-terminal sequences and of the inserted sequence of Pe-61 and were immunoadsorbed until they became monoreactive. By western blot analysis, the peripherin isoforms were localised in neuroblastoma NB2a cell lysates and detergent insoluble fractions separated by two-dimensional electrophoresis. In addition, each isoform was resolved into several charge variants. At the cellular level, each antibody decorated the filament array of the NB2a cells, suggesting the participation of the minor peripherin isoforms in the intermediate filament network.

Animals↗