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PubMed1993

Ontogenesis of type II spiral ganglion neurons during development: peripherin immunohistochemistry.

In this study, we analysed the distribution of the intermediate filament peripherin in the developing cochlea of the rat. At gestational day 16, weak immunolabeling was observed in neuronal somas throughout the spiral ganglion. At gestational day 20, the peripherin labeling increased in intensity throughout the spiral ganglion. At gestational day 20, the peripherin labeling increased in intensity throughout the cochlea but became especially strong in some ganglion neurons of the basal turn. Homogeneous immunolabeling was observed throughout the spiral ganglion of the apical turn. Double immunofluorescence labeling of the prenatal cochlea with peripherin and neurofilament (NF) antibodies revealed colocalization on the same structures. By postnatal day 3, the peripherin labeling intensity had decreased in the majority of spiral ganglion neurons, but remained strong in some cells of the basal turn. Only a few neurons continued to be immunolabeled into adulthood that correspond to Type II spiral ganglion neurons expressing both NF protein and peripherin, two classes of intermediate filament proteins. In the organ of Corti, the first immunolabeling was observed on gestational day 20 as peripheral fibers reaching the receptor cells. Positive fibers were observed below both inner (IHCs) and outer (OHCs) hair cells. At birth and at postnatal day 3, peripherin immunolabeling was still observed below both IHCs and OHCs. By postnatal day 4, peripherin labeling became more dominant in fibers below OHCs, but some immunoreactivity was still present below IHCs. No immunoreactivity was present in the intraganglionic spiral bundle (IGSB) fibers containing the olivary complex efferent fibers before birth. A few days after birth some fibers of the IGSB started to be immunoreactive.

Animals↗
PubMed1998

Peripherin-like immunoreactivity in type II spiral ganglion cell body and projections.

Peripherin, an intermediate filament protein, is present in neuronal subpopulations of both peripheral and central nervous systems. The distribution of peripherin was studied in the adult rat cochlea using immunohistochemistry on whole mount material, in cryostat sections and sections of plastic embedded tissue. In the spiral ganglion, peripherin labeling was restricted to the perikarya of a subpopulation of neurons and their peripheral and central processes. Peripherin positive neurons had the following features: (i) they have a large eccentric nucleus, they were often found in a cluster of 2 or 3 cells, (ii) they were often located near the intraganglionic spiral bundle fibers, (iii) they represented roughly 8% of the whole ganglion population and (iv) on the average they had smaller perikarya than non-immunoreactive cells. Immunostaining on semithin plastic sections revealed positive reactivity on Type II ganglion cells, while Type I neurons were negative. Double labeling using peripherin and three neurofilament (NF) subunit antibodies confirmed the presence of both markers within the same spiral ganglion cell type. Type II neurons have been previously documented as the only subpopulation of the spiral ganglion that presents a strong positive NF immunoreactivity within their perikarya. In the organ of Corti, peripherin-positive fibers formed bundles that course beneath the outer hair cells and send branches that end as boutons contacting the outer hair cells. All these characteristics suggest that peripherin-positive cells are Type II neurons, and that peripherin constitutes a reliable marker for this spiral ganglion subpopulation, as well as their peripheral and central processes.

Animals↗
PubMed1992

Neurite outgrowth in peripherin-depleted PC12 cells.

Peripherin is the major neuronal intermediate filament (IF) protein in PC12 cells and both its synthesis and amount increase during nerve growth factor (NGF) promoted neuronal differentiation. To address the question of the biological function of peripherin in neurite initiation we have used an antisense oligonucleotide complementary to the 5' region of peripherin mRNA to specifically inhibit its transcription. The oligonucleotide blocks both the synthesis of peripherin and its increase in response to NGF. Peripherin was found to be a stable protein with a cellular half-life of approximately 7 d. 6 wk of incubation with the oligonucleotide decreases peripherin to 11% of the level in naive control cells and to 3% of that in NGF-treated control cells. Despite the depletion, NGF elicits apparently normal neurite outgrowth from the oligonucleotide-treated cells. As evaluated by EM, there are few IFs in these cells, either in the cell bodies or neurites. There is no compensatory increase in NF-M, NF-L, or vimentin levels as a result of the inhibition of peripherin synthesis. These findings suggest that peripherin is not required for neurite formation, but is necessary for the formation of a cellular IF network which could be involved in process stability. They also demonstrate the utility of antisense oligonucleotides for the study of proteins with long half-lives.

Animals↗
PubMed1997

Differential expression of the intermediate filament peripherin in cutaneous neural lesions and neurotized melanocytic nevi.

Peripherin is an intermediate filament involved in growth and development of the peripheral nervous system, and is produced by neurons and the beta cells of the islets of Langerhans. Recently, malignant melanomas and some melanocytic nevi have been shown to express peripherin. It is unknown if Schwann cells, also derived from the neural crest, express peripherin. Expression of peripherin was evaluated by immunohistochemistry in cutaneous lesions characterized by a prominent Schwann cell component including 26 neurofibromas (NF), 10 schwannomas (SCH), seven granular cell tumors, and five palisaded encapsulated neuromas (PEN); 13 neurotized melanocytic nevi (NMN) also were evaluated because these lesions contain Wagner-Meissnerlike structures and type C nevus cells, which exhibit a "schwannian" phenotype. Peripherin was detected in the axons of normal peripheral nerves. NF and PEN contained numerous axons dispersed throughout the lesions, whereas only scattered small nerves were seen in GCT. In SCH, only rare axons were labeled, mostly at the periphery of the lesions. All other cells in these four types of lesions, therefore including Schwann cells, were not labeled. In most NMN, labeled axons were identified within the lesions. In a few cases, rare epithelioid melanocytes within the superficial portions of the nevi were labeled. The Wagner-Meissnerlike structures and type C nevus cells (schwannian) were not labeled in any lesion; however, numerous labeled axons invested these areas. Because there are different relative numbers of peripherin-labeled axons throughout NF, PEN, some nevi, and SCH, analysis of peripherin expression may be helpful in the diagnosis of these lesions. Neurons and some epithelioid melanocytes, in contrast to type C nevus cells and Schwann cells of NF and SCH, express peripherin, providing further evidence for a transition from a more neuronal to a more schwannian phenotype during the normal maturation sequence of melanocytes in nevi.

Axons↗
PubMed1992

Cell-specific transcription of the peripherin gene in neuronal cell lines involves a cis-acting element surrounding the TATA box.

Peripherin is a neurone-specific intermediate filament protein expressed mostly in the peripheral nervous system. To localize sequences that are important for the regulation of peripherin gene transcription, we have functionally dissected its promoter. Transfection into different cell lines and deletion mapping of peripherin-lacZ hybrid constructs indicated that the first 98 bp preceding the transcription start site of the gene were sufficient to confer cell-type specific expression. DNase I footprinting experiments revealed three protected sequences in this region, that were named PER1, PER2 and PER3. The PER2 and PER3 elements, localized between -98 to -46, interact with proteins that seem widely distributed. Deletion of these elements severely decreased the level of reporter gene activity. The PER1 element, which overlaps the TATA box, interacts with a DNA-binding protein prevailing in peripherin expressing cell lines. However, the core promoter, which contains the PER1 element, was inefficient in driving gene expression. Experiments designed to test the contribution of each element showed that PER2 and PER3 were important in determining the level of expression, while PER1 was important for cell-type specificity. In fact the polyoma virus enhancer linked to the peripherin gene core promoter was found to limit reporter gene activity to peripherin expressing cell lines. Together, these experiments indicate that co-operative interactions between different regions of the promoter are necessary for efficient and cell-type specific transcription of the peripherin gene in a subset of neuronal cells.

Animals↗
PubMed1991

NF-L and peripherin immunoreactivities define distinct classes of rat sensory ganglion cells.

Double immunofluorescence studies using antibodies against NF-L and peripherin revealed three distinct subpopulations of neurons in rat dorsal root ganglia (DRG). In the adult rat, 46% of the DRG neurons were small and peripherin-positive (NF-L-negative), and 48% were large and NF-L-positive (peripherin-negative). About 6% were both peripherin- and NF-L-positive. All of the DRG neurons reacted with antibodies to NF-M and nonphosphorylation-dependent or phosphorylation-independent antibodies to NF-H. The neuropeptides were predominantly found in the peripherin-positive small cell population. Eighty-seven percent of the peripherin-positive small cell population contained substance P immunoreactivity, while 43% of this cell population contained CGRP. In contrast, only 18-24% of the NF-L-positive large-cell population contained neuropeptides, and these were primarily in a smaller sized subpopulation. Similar patterns of antigen representation were observed in neonatal (PN2) DRG cell populations. Tissue cultures of sensory ganglion cells from PN2 DRG, in serum-free medium, stably maintained exclusively peripherin-positive neurons, with about 5% of these containing coexistent NF-L immunoreactivity. Very high levels of neuropeptide gene expression were exhibited by these postnatal neurons in culture.

Aging↗
PubMed1994

The structure of the human peripherin gene (PRPH) and identification of potential regulatory elements.

We determined the complete nucleotide sequence of the coding region of the human peripherin gene (PRPH), as well as 742 bp 5' to the cap site and 584 bp 3' to the stop codon, and compared its structure and sequence to the rat and mouse genes. The overall structure of 9 exons separated by 8 introns is conserved among these three mammalian species. The nucleotide sequences of the human peripherin gene exons were 90% identical to the rat gene sequences, and the predicted human peripherin protein differed from rat peripherin at only 18 of 475 amino acid residues. Comparison of the 5' flanking regions of the human peripherin gene and rodent genes revealed extensive areas of high homology. Additional conserved segments were found in introns 1 and 2. Within the 5' region, potential regulatory sequences, including a nerve growth factor negative regulatory element, a Hox protein binding site, and a heat shock element, were identified in all peripherin genes. The positional conservation of each element suggests that they may be important in the tissue-specific, developmental-specific, and injury-specific expression of the peripherin gene.

Amino Acid Sequence↗
PubMed1990

Regulation of peripherin and neurofilament expression in regenerating rat motor neurons.

Northern blotting, in situ hybridization and immunocytochemistry were used to study the changes in levels of mRNA coding for peripherin and in immunoreactivity of peripherin, a type III neuronal intermediate filament, in rat spinal motor neurons following axotomy of the sciatic nerve. For comparison, parallel studies examined the biology of neurofilament (NF) proteins in this model. The sciatic nerve was crushed at the junction of the L4-L5 spinal nerves. Levels of messenger RNA (mRNA) coding for peripherin in the motor neurons doubled by 4 days postaxotomy and remained elevated for a period of 6 weeks. Within 4-7 days of injury peripherin immunoreactivity increased significantly in cell bodies of motor neurons and remained elevated through 6 weeks. In contrast, no changes were detected in NF-M immunoreactivity over the same time period. By 8 weeks postaxotomy, levels of peripherin mRNA and protein returned to control values. The increases in the expression of peripherin parallel those of beta-tubulin and actin, and these changes are quite different from the alterations in neurofilament mRNA that decrease after axotomy. The contrasting responses of peripherin and NF to nerve injury indicates that each of these intermediate filaments may play distinct roles in nerve growth and regeneration.

Animals↗
PubMed1990

The expression of the neuronal intermediate filament protein peripherin in the rat embryo.

The expression of the neuronal type III intermediate filament protein peripherin was examined in the rat embryo during and following neuronogenesis in the spinal cord and the peripheral nervous system. In situ hybridization analysis reveals that peripherin mRNA is found in the mid-gestational rat embryo in ventral and lateral motoneurons in the spinal cord, and in neurons of all peripheral ganglia examined, including spinal, sympathetic, and enteric ganglia. Peripherin mRNA is seen only in post-migratory motoneurons or neuronal cells in aggregating ganglia, indicating that precursor cells do not express peripherin. To examine the expression of the protein, an affinity-purified antibody (anti-per) specific for a bacterially produced peripherin fusion protein was generated. Anti-per specifically recognizes a 58 kDa, cytoskeletal-enriched, nerve growth factor (NGF)-inducible protein of the expected tissue distribution. Immunocytodetection with anti-per shows that the initiation of peripherin protein synthesis is coincident with the morphological differentiation of neurons. In development, peripherin is one constituent of a program of gene expression activated at terminal neuronal differentiation.

Animals↗
PubMed1989

Immunocytochemical localization of the intermediate filament protein peripherin in adult mouse adrenal chromaffin cells in culture.

Peripherin is the main intermediate filament protein in sympathetic neurons. Immunoreactivity to peripherin was studied in mouse adrenal chromaffin cells after 6 days in culture, and compared to immunoreactivity to tyrosine hydroxylase used as a general marker of chromaffin cells in culture. Most of the cells immunoreactive to tyrosine hydroxylase were rounded, with a glandular phenotype and a few of them had processes. The cells reactive to peripherin only constituted a small proportion of the chromaffin cells (2%), and most of them sent out processes. However, not all the cells with processes were reactive for peripherin. These results did not change in the presence of nerve growth factor. The discussion focuses on the significance of the sub-population of cells reactive to peripherin. We suggest that these cells resemble the small granule chromaffin cells, regarded as an intermediate cell type between glandular cells and neurons. The cells that expressed peripherin here are compared to those selected to form the PC12 clone. The presence of peripherin in only a few of the cells sending out neurite-like processes is discussed in relation to the expression of other neurofilament proteins in developing cells and to the influence of non-chromaffin cells.

Adrenal Medulla↗
PubMed1989

Structure of the gene encoding peripherin, an NGF-regulated neuronal-specific type III intermediate filament protein.

We have cloned the rat gene encoding peripherin, a neuronal-specific intermediate filament protein that is NGF-regulated. Determination of the complete sequence, including 821 nucleotides of the 5'-flanking region, allows us to make conclusions about the evolutionary origin of the peripherin gene, its homology with other intermediate filament proteins, and possible mechanisms of regulation of peripherin expression in neurons. The positions of the eight peripherin gene introns correspond to the intron patterns of desmin, vimentin, and GFAP, with one example of intron sliding. Together with protein sequence homologies, this conclusively demonstrates that peripherin is a type III intermediate filament protein. The peripherin promoter contains sequences homologous to regions of other NGF-regulated promoters, which may function in peripherin induction by NGF.

Amino Acid Sequence↗
PubMed1994

Expression of the neural intermediate filament proteins peripherin and neurofilament-66/alpha-internexin in neuroblastoma.

BACKGROUND: Peripherin and neurofilament (NF)-66/alpha-internexin are recently characterized, neuron-specific intermediate filament proteins that are expressed in the developing peripheral nervous system. Peripherin, in particular, is highly enriched in neuronal derivatives of the neural crest. We speculated that these intermediate filament proteins would be expressed in neuroblastoma (NB), a neural crest-derived tumor with many neuronal features. EXPERIMENTAL DESIGN: By use of antibodies specific to peripherin and NF-66/alpha-internexin, we detected these proteins on Western blots of NB tissue extracts and in paraffin sections of NBs. RESULTS: Western blotting indicated that NB tumor extracts contained immunoreactive proteins that co-migrated with rat peripherin and human NF-66/alpha-internexin from normal tissues, thus establishing the specificity of the antibodies for these proteins in tumors. The antibody specific for peripherin labeled all NBs, including immature NBs, composite ganglioneuroblastomas and ganglioneuromas. In contrast, the NF-66/alpha-internexin antibody labeled only 50% of NBs, and only weakly labeled most ganglioneuroblastomas and ganglioneuromas. Neither antibody labeled other small blue cell tumors such as lymphomas, rhabdomyosarcomas, Wilms' tumors, and Ewing sarcomas. CONCLUSIONS: The specificity of the peripherin labeling of NB and the ability of the peripherin antibody to label the entire spectrum of NBs, including ganglioneuroblastomas and ganglioneuromas, indicate that this intermediate filament protein has potential as a diagnostic marker for these related neural crest neoplasms.

Animals↗
PubMedDate not supplied

Peripherin: a novel marker for the immunohistochemical study of malformations of the enteric nervous system.

Pheripherin is a 57-kD type III intermediate filament that is a specific marker for peripheral neruons, including enteric ganglion cells (GCs). Hence antibodies to peripherin may be used to demonstrate abnormalities of the enteric nervous system (ENS). Serial longitudinal histologic sections of formalin-fixed paraffin-embedded colons from 15 patients were immunostained for peripherin, neuron-specific enolase (NSE), neurofilaments, S-100, and synaptophysin. Ten patients had variable degrees of colonic aganglionosis (Hirschsprung's disease), three were premature in infants, and two were controls. Peripherin labeling yielded the highest number of recognizable GCs. Overall, 56%, 78%, and 80% of the peripherin-positive GCs in the myenteric plexus were identified by staining for neurofilaments, NSE, and S-100, respectively. Intramucosal GCs were detected in 4 of 10 cases of Hirschspring's disease (HD), none of which had been evident by routine histology. The other neuronal markers were less specific for intramucosal GCs than peripherin, because they also added enterochromaffin cells. Peripherin immunohistochemistry also allowed exact quantification of GC density expressed as GCs/mm colon, which is important for the diagnosis of HD-related disorders. In three cases of HD the GC density of the transition zone was markedly elevated compared with more proximal ganglionic bowel segments, consistent with neuronal intestinal dysplasia type B, and two cases of HD showed low GC density within the transition zone. Hence peripherin immunolabeling may prove to be a valuable aid in the diagnosis and classification of congenital malformations of the ENS.

Biomarkers↗
PubMed1994

Axonal transport of type III intermediate filament protein peripherin in intact and regenerating motor axons of the rat sciatic nerve.

Slow axonal transport of peripherin has been studied in the motor axons of both intact and regenerating rat sciatic nerves 7 days post-crush. The studies were done by two-dimensional gel electrophoresis after intraspinal injection of 35S-methionine. In the first experiment, the sciatic nerves were removed 3 weeks after the radiolabeling pulse and cut into 6 mm segments. Each nerve segment was submitted to two-dimensional gel electrophoresis and analyzed by an original procedure which allowed us to study the distribution along the nerve of the radioactivity associated with several proteins of the cytoskeleton, especially the intermediate filament proteins, peripherin, and the low molecular mass neurofilament protein, NF-L. Peripherin was transported at two main rates: 66% of the total radiolabeled peripherin moved at 1.42 mm/day and the remainder moved at 2.28 mm/day. The radioactivity associated with NF-L exhibited a similar pattern. In the second experiment, similar intraspinal injections were made 7 days after a unilateral crush of the sciatic nerve. Regenerating nerves exhibited a clear SCa wave. However, in contrast to the intact nerves, the SCb wave could not be precisely defined in the regenerating nerves. Thus, the changes in the amount of transported proteins were analyzed in the SCa wave only. Autoradiograms of 2D-PAGE revealed that in the regenerating axons, the quantity of transported peripherin in SCa was increased by 3.5-fold. In contrast, the quantity of transported NF-L was decreased by 1.6-fold. The regenerating motor axons conveyed significantly greater (approximately twofold) amounts of labeled tubulins and actin than did intact motor axons. Our results suggest that peripherin, although mainly conveyed by SCa, plays a role during the elongation process in addition to actin and tubulin.

Animals↗
PubMed1995

Distribution of neurofilament proteins and peripherin in the rat pituitary gland.

The distribution of neurofilament proteins and peripherin in the pituitary gland of the rat was studied with a panel of monoclonal and polyclonal antibodies recognizing different neurofilament subunits. In the posterior lobe, a dense plexus of neurofilament- and peripherin-immunoreactive fibers was seen. In the intermediate lobe neurofilament- and peripherin-immunoreactivity was seen only in nerve fibers in the connective tissue septa, while no immunoreactivity was seen in parenchymal nerve fibers. Bilateral sympathetic ganglionectomy did not affect peripherin-immunoreactivity, indicating that the peripherin-immunoreactive fibers are of central origin. In the anterior lobe, a few solitary neurofilament- and peripherin-immunoreactive fibers were observed. Western blotting confirmed the presence of 150 kD and 200 kD neurofilament proteins in the posterior lobe. No neurofilament protein was detected in the intermediate and anterior lobes. Abundant intermediate filaments were seen with electron microscopy in the nerve fibers of the connective tissue septa in the intermediate lobe. In the parenchymal nerve fibers only microtubules were seen, indicating that the lack of neurofilament immunoreactivity is due to absence of neurofilaments.

Animals↗
PubMed2000

Expression of the intermediate filament peripherin in extraskeletal myxoid chondrosarcoma.

The embryologic histogenesis of cartilage is not well characterized. While cranial cartilage is believed to be derived from pluripotential precursor cells of the neural crest, chondrocytes found elsewhere in the body are thought to be derived from mesoderm. As such, soft tissue tumors with cartilaginous differentiation may be related to neural crest or mesoderm. Peripherin is an intermediate filament encoded on chromosome 12, involved in growth and development of the peripheral nervous system. Peripherin is apparently expressed exclusively in cells derived from the neural crest and neural tube. A group of six soft tissue tumor types was selected because they are either of controversial differentiation or cytogenetically related to chromosome 12. A total of 41 cases was evaluated with antibodies against the intermediate filament peripherin. A panel of neural and neuroendocrine differentiation markers was used in selected cases. Three of five extraskeletal myxoid chondrosarcomas showed strong cytoplasmic reactivity with anti-peripherin. No peripherin expression was noted in any of eleven epithelioid sarcomas, eight liposarcomas, seven conventional chondrosarcomas, four neurothekeomas, three alveolar soft part sarcomas, or three clear cell sarcomas. The finding of peripherin expression in some extraskeletal myxoid chondrosarcomas may suggest the ability of some tumors to demonstrate both neural and chondroid differentiation.

Adolescent↗
PubMed1996

The TATA motif is a target for efficient transcriptional activation and nerve growth factor induction of the peripherin gene.

Three proximal elements, PER1, PER2, and PER3, have been implicated in the regulation of peripherin gene expression. PER1 contains the TATA motif and was identified as the principal mediator of neuronal specificity. Here, we demonstrate by transfection of constructs mutated in PER1 that the in vitro protein binding activity of PER1 is irrelevant to its function. However, mutations or substitutions in the TATA box decreased promoter activity by up to 80%. We have investigated this unusual preference for a particular TATA sequence in PC12 cells. In these cells, nerve growth factor induces neuronal differentiation, increasing peripherin gene expression 3-4-fold, while dexamethasone elicits chromaffin differentiation and a 3-fold decrease in peripherin mRNA. Experiments with stably transfected PC12 cells revealed that the specific TATA box of the peripherin gene was crucial for nerve growth factor response. However, it did not affect dexamethasone down-regulation. Therefore, nerve growth factor acts through an element essential for neuronal peripherin gene expression. The results predict that proteins interacting in the vicinity of the TATA box, by inference factors associated with the preinitiation complex, are important for peripherin gene regulation and provide new insights into the mechanisms underlying neuronal differentiation.

Animals↗
PubMed2001

Molecular characterization of peripherin-2 and rom-1 mutants responsible for digenic retinitis pigmentosa.

Peripherin-2 and Rom-1 are homologous tetraspanning membrane proteins that assemble into noncovalent tetramers and higher order disulfide-linked oligomers implicated in photoreceptor disc morphogenesis. Individuals who coinherit a L185P peripherin-2 mutation and a null or G113E rom-1 mutation are afflicted with retinitis pigmentosa, whereas individuals who inherit only one defective gene are normal. We examined the expression, subunit assembly, and disulfide-mediated oligomerization of L185P and L185A peripherin-2 and L188P Rom-1 by velocity sedimentation, co-immunoprecipitation, and cross-linking. These mutants formed noncovalent dimers under disulfide-reducing conditions but failed to assemble into core tetramers. Under nonreducing conditions, L185P dimers formed disulfide-linked tetramers but not higher order oligomers. L185P coassembled with wild-type peripherin-2 and Rom-1 to form tetramers and higher order disulfide-linked oligomers characteristic of the wild-type proteins. The G113E Rom-1 mutant expressed 20-fold lower than wild-type Rom-1, indicating that it behaves mechanistically as a null allele. We conclude that Leu(185) of peripherin-2 (Leu(188) of Rom-1) is critical for tetramer but not dimer formation and that the core tetramer has 2-fold symmetry. Peripherin-2-containing tetramers are required for higher order disulfide-linked oligomer formation. The level of these oligomers is critical for stable photoreceptor disc formation and the digenic retinitis pigmentosa disease phenotype.

Animals↗