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PubMed2000

Ectopic expression of luteinizing hormone-releasing hormone and peripherin in the respiratory epithelium of mice lacking transcription factor AP-2alpha.

The vertebrate transcription factor activator protein-2 (AP-2alpha) is involved in craniofacial morphogenesis. In the nasal placode AP-2alpha expression delineates presumptive respiratory epithelia from olfactory epithelia, with AP-2alpha expression restricted to the anterior region of the respiratory epithelium (absent from the olfactory epithelium) at later stages. To address the role AP-2alpha plays in differentiation of cell groups in the nasal placode, the spatiotemporal expression pattern of four markers normally associated with olfactory epithelial structures was analyzed in mice lacking AP-2alpha. These markers were the intermediate filament protein peripherin, the neuropeptide luteinizing hormone-releasing hormone (LHRH), the neural cell adhesion molecule (NCAM) and the olfactory transcription factor Olf-1. Development of cells expressing these markers was similar in both genotypes until embryonic day 12.5 (E12.5), indicating that the main olfactory epithelium and olfactory pit formation was normal. At E13.5 in mutant mice, ectopic LHRH neurons and peripherin axons were detected in respiratory epithelial areas, areas devoid of Olf-1 and NCAM staining. Over the next few days, an increase in total nasal LHRH neurons occurred. The increase in nasal LHRH neurons could be accounted for by LHRH neurons arising and migrating out of respiratory epithelial regions on peripherin-positive fibers. These results indicate that AP-2alpha is not essential for the separation of the olfactory and respiratory epithelium from the nasal placode and is consistent with AP-2alpha preventing recapitulation of developmental programs within the respiratory epithelium that lead to expression of LHRH and peripherin phenotypes.

Animals↗
PubMed1990

Molecular cloning, primary structure, and orientation of the vertebrate photoreceptor cell protein peripherin in the rod outer segment disk membrane.

Peripherin, a 39-kDa membrane protein, has been previously localized to the rim region of the vertebrate rod photoreceptor disk membrane by use of monoclonal antibodies and immunocytochemical labeling techniques. As an initial step in determining the structure and function of this protein, we have cloned and sequenced cDNA containing its complete coding sequence. A bovine retinal lambda gt11 expression library was screened with the antibodies, and a 583 base pair clone was initially isolated. The remaining part of the coding sequence was obtained from subsequent rescreenings of the same library and an independent lambda gt10 library. A C-terminal CNBr fragment of peripherin was purified by immunoaffinity chromatography and reverse-phase high-performance liquid chromatography. The amino acid sequence of the isolated C-terminal peptide and the N-terminal sequence analysis of immunoaffinity-purified peripherin are in agreement with the cDNA sequence. The cDNA sequence predicts that there are possibly four transmembrane domains. On the basis of immunocytochemical studies and sequence analysis, the hydrophilic C-terminal segment containing the antigenic sites for the antiperipherin monoclonal antibodies has been localized on the cytoplasmic side of the disk membrane. There are three consensus sequences for asparagine-linked glycosylation. Deglycosylation studies have indicated that at least one of these sites is utilized. The possible function of peripherin in relation to its primary structure is discussed.

Amino Acid Sequence↗
PubMed1998

Ultrastructural studies of carboxyl-terminal truncation mutants of the neuronal intermediate filament protein peripherin.

We have prepared carboxyl-terminal truncation mutants of the neuronal intermediate filament (IF) protein peripherin and examined the assembly characteristics of these mutant proteins in SW13 cells in the presence and absence of vimentin. In the absence of vimentin, tailless peripherin protein (Per-C424) self-assembles into bundles and clumps as observed by immunofluorescence, whereas a peripherin mutant that is missing the tail as well as a small portion of the rod (Per-C356) appears as spherical aggregates. Similar phenotypes are observed when vimentin-positive cells are transfected with Per-C424 or Per-C356. In these cells, the entire IF network is disrupted, and vimentin colocalizes with the mutant peripherin proteins. To examine the morphology of the bundles and clumps formed by Per-C424 at the electron microscopic level, we prepared stable cell lines expressing different levels of this mutant protein. By immunofluorescence, Per-C424 appears as either clumps or bundles of filaments depending on the expression level of the mutant protein. However, under electron microscopy, it is apparent that both clumps and bundles are composed of tightly packed IFs. We were unable to obtain stable cell lines expressing Per-C356, indicating that this mutant may prevent cell proliferation. Using a vector containing an internal ribosomal entry site, we prepared a construct that expresses Per-C356 and green fluorescent protein as a single mRNA, and we were able to isolate cells that expressed Per-C356 by fluorescence-activated cell sorting. Electron microscopic analysis of these cells showed that these aggregates are solid and contain no obvious filamentous structures.

Cell Line↗
PubMed2003

Peripherin-mediated death of motor neurons rescued by overexpression of neurofilament NF-H proteins.

In previous studies, we showed that overexpression of peripherin, a neuronal intermediate filament (IF) protein, in mice deficient for neurofilament light (NF-L) subunits induced a progressive adult-onset degeneration of spinal motor neurons characterized by the presence of IF inclusion bodies reminiscent of axonal spheroids found in amyotrophic lateral sclerosis (ALS). In contrast, the overexpression of human neurofilament heavy (NF-H) proteins provoked the formation of massive perikaryal IF protein accumulations with no loss of motor neurons. To further investigate the toxic properties of IF protein inclusions, we generated NF-L null mice that co-express both peripherin and NF-H transgenes. The axonal count in L5 ventral roots from 6 and 8-month-old transgenic mice showed that NF-H overexpression rescued the peripherin-mediated degeneration of motor neurons. Our analysis suggests that the protective effect of extra NF-H proteins is related to the sequestration of peripherin into the perikaryon of motor neurons, thereby abolishing the development of axonal IF inclusions that might block transport. These findings illustrate the importance of IF protein stoichiometry in formation, localization and toxicity of neuronal inclusion bodies.

Amyotrophic Lateral Sclerosis↗
PubMed1999

The intermediate filament protein peripherin is the specific interaction partner of mouse BPAG1-n (dystonin) in neurons.

The dystonia musculorum (dt) mouse suffers from severe degeneration of primary sensory neurons. The mutated gene product is named dystonin and is identical to the neuronal isoform of bullous pemphigoid antigen 1 (BPAG1-n). BPAG1-n contains an actin-binding domain at its NH2 terminus and a putative intermediate filament-binding domain at its COOH terminus. Because the degenerating sensory neurons of dt mice display abnormal accumulations of intermediate filaments in the axons, BPAG1-n has been postulated to organize the neuronal cytoskeleton by interacting with both the neurofilament triplet proteins (NFTPs) and microfilaments. In this paper we show by a variety of methods that the COOH-terminal tail domain of mouse BPAG1 interacts specifically with peripherin, but in contrast to a previous study (Yang, Y., J. Dowling, Q.C. Yu, P. Kouklis, D.W. Cleveland, and E. Fuchs. 1996. Cell. 86:655-665), mouse BPAG1 fails to associate with full-length NFTPs. The tail domains interfered with the association of the NFTPs with BPAG1. In dt mice, peripherin is present in axonal swellings of degenerating sensory neurons in the dorsal root ganglia and is downregulated even in other neural regions, which have no obvious signs of pathology. Since peripherin and BPAG1-n also display similar expression patterns in the nervous system, we suggest that peripherin is the specific interaction partner of BPAG1-n in vivo.

Animals↗
PubMed1997

Expression of peripherin, NADPH-diaphorase and NOS in the adult rat neocortex.

Peripherin is mainly expressed in peripheral neurones and in CNS neurones which extend axons into peripheral nerves. However, this intermediate filament protein has also been detected in a few other neurones entirely located within the CNS. The present study focuses on the adult rat neocortex. Peripherin immunoreactive (P+) neuronal somata and their neuritic extensions were observed in cortical layers II, III, V and VI, while a few P+ nerve fibres could be seen in layer I. All the P+ neurones could be selectively stained using reduced nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry, a typical feature of aspiny neurones. Some of the P+ neurones could also be immunostained with an antibody raised against nitric oxide synthase (NOS). These results provide evidence that peripherin is present in a discrete population of aspiny interneurones of the adult rat neocortex. The functional significance of the co-expression of peripherin and NOS needs further investigation.

Animals↗
PubMed1992

Autosomal dominant retinitis pigmentosa (adRP; RP6): cosegregation of RP6 and the peripherin-RDS locus in a late-onset family of Irish origin.

We recently reported the localization of a gene for late-onset autosomal dominant retinitis pigmentosa (adRP; RP6), on the short arm of chromosome 6, by linkage analysis in a large family of Irish origin. It is notable that the gene encoding peripherin-RDS, a photoreceptor-specific protein, recently has been physically mapped on 6p. In our own analysis, an intrageneic marker derived from this gene cosegregated with the adRP disease locus with zero recombination (lod score 5.46 at q = .00). Using the CEPH reference panel, we now report the mapping of the peripherin-RDS gene relative to other 6p markers in the CEPH data base. Incorporation of these data into a multipoint analysis produced a lod score for adRP of 8.21, maximizing at the peripherin-RDS locus. This study provides strong evidence suggesting a role for peripherin-RDS in the etiology of one form of adRP.

Base Sequence↗
PubMed1995

Translation initiation and assembly of peripherin in cultured cells.

The peripherin gene has three potential ATG translation initiation sites at positions 38, 56, and 290. The second ATG has been proposed to be the initiation codon used for translation of the protein, but there is no experimental evidence for this conjecture. We have isolated a full-length peripherin cDNA (designated as p61-11) from a rat brain cDNA library. Upon sequencing, we found that this cDNA contains a point mutation at the second potential translation initiation codon, which changes this ATG to ACG. When expressed in SW13 cl.2 vim- cells, a cell line without any detectable cytoplasmic intermediate filaments, the protein product of p61-11 cannot form a filamentous network and the major product is 45 kDa in size, which is most likely initiated from the third ATG. The protein product from the first ATG (57 kDa in size) of p61-11 is also detected albeit in smaller amounts. We introduced a frame-shift mutation upstream of the third ATG in p61-11 to create p61-11FS and showed that the third ATG is able to initiate translation efficiently even in the presence of the first ATG, and the 45 kDa protein leads to a diffuse nonfilamentous staining pattern in vim- cells confirming that the first ATG may not be the preferred translation initiation codon, since it cannot suppress a downstream ATG. We increased the translation efficiency from the first ATG of p61-11 by mutating the three nucleotides preceding this first ATG and thereby placing it in a better Kozak consensus sequence for translation initiation. The resulting 57 kDa protein is able to form a filamentous network in vim- cells. We corrected the mutation in the original p61-11 by polymerase chain reaction and generated two peripherin constructs: perM1M2 (which contains all three translation initiation codons) and per delta 1M2 (the first ATG is deleted, but the other two are present). When transfected, their protein products, about 57 kDa in size, form filamentous networks in the absence of other cytoplasmic intermediate filaments. Since there is no 45 kDa protein detected for these latter two constructs, it is reasonable to conclude that in the presence of the second ATG, little or no translation is initiated from the third ATG. Taken together, these results strongly suggest that the second ATG is the preferred translation initiation codon for the peripherin gene.

Adenocarcinoma↗
PubMed1996

Peripherin fibers in the main olfactory bulb are different from olfactory fibers and from LHRH fibers: an immunocytochemical and DiI study.

Fibers coming from the olfactory epithelium and entering the olfactory bulb expressed peripherin. These were not sensory olfactory fibers because: (1) they did not form glomeruli, (2) they did not express olfactory marker protein (OMP), (3) they entered deeply into the olfactory bulb, reaching its white matter. Cells and fibers in the olfactory bulb expressing luteinizing hormone-releasing hormone (LHRH) differed from those expressing peripherin because LHRH and peripherin did not coexist and the distributions of LHRH-positive and peripherin-positive fibers were found to be different.

Animals↗
PubMed1994

Expression of peripherin in solid transplants of foetal spinal cord and dorsal root ganglia grafted to the injured cervical spinal cord of adult rats.

The expression of the neuronal type III intermediate filament protein peripherin was studied in E14 spinal cord fragments and E15 dorsal root ganglia 1-30 weeks after their transplantation to the injured cervical spinal cord of the adult rat. In the dorsal root ganglion transplants, the surviving neurons generally appeared as a rather healthy looking population of small strongly immunoreactive cells which are very similar to the small dorsal root ganglion neurons of adult control rats. In the spinal cord transplants, there were only a few peripherin-immunoreactive neurons, morphologically close to the motoneurons or to the preganglionic sympathetic neurons of adult rats. In both types of transplants, peripherin expression of the immunoreactive neurons was apparently correlated with the previously established ability of these transplanted neurons for extensive axonal growth into a co-grafted peripheral nerve.

Animals↗
PubMed1998

Expression of the gene for the retinal protein peripherin in the pineal gland of humans and Djungarian hamsters (Phodopus sungorus).

This study investigated whether the gene for peripherin, a protein previously considered to play only a role in the retina, may also be expressed in the pineal gland of both Djungarian hamsters (Phodopus sungorus) and humans. After extraction of mRNA from pooled pineal glands of hamsters and from one human pineal gland, mRNA was transcribed into cDNA followed by PCR amplification with specific primers. Clear signals were obtained at the expected sizes of the PCR products. An additional experiment in hamsters revealed that the peripherin gene is expressed throughout the entire 24-h period. Since peripherin is an important protein in the retina stabilizing the photoreceptor discs it is speculated that this protein might also play a structural role in the pineal gland.

Animals↗
PubMed1991

A three-base-pair deletion in the peripherin-RDS gene in one form of retinitis pigmentosa.

The group of retinopathies termed retinitis pigmentosa (RP) greatly contribute to visual dysfunction in man with a frequency of roughly 1 in 4,000. We mapped the first autosomal dominant RP (adRP) gene to chromosome 3q, close to the gene encoding rhodopsin, a rod photoreceptor pigment protein. Subsequently, mutations in this gene have been implicated as responsible for some forms of adRP. Another adRP gene has been mapped to chromosome 8p. A third adRP gene in a large Irish pedigree has been mapped to chromosome 6p, showing tight linkage with the gene for peripherin, a photoreceptor cell-specific glycoprotein, which is thus a strong candidate for the defective gene. We have now identified a three-base-pair deletion which results in the loss of one of a pair of highly conserved cysteine residues in the predicted third transmembrane domain of peripherin. This deletion segregates with the disease phenotype but is not present in unaffected controls, and suggests that mutant peripherin gives rise to retinitis pigmentosa.

Amino Acid Sequence↗
PubMed1991

Photoreceptor peripherin is the normal product of the gene responsible for retinal degeneration in the rds mouse.

Retinal degeneration slow (rds) is a retinal disorder of an inbred strain of mice in which the outer segment of the photoreceptor cell fails to develop. A candidate gene has recently been described for the rds defect [Travis, G. H., Brennan, M. B., Danielson, P. E., Kozak, C. & Sutcliffe, J. G. (1989) Nature (London) 338, 70-73]. Neither the identity of the normal gene product nor its intracellular localization had been determined. We report here that the amino acid sequence of the bovine photoreceptor-cell protein peripherin, which was previously localized to the rim region of the photoreceptor disk membrane, is 92.5% identical to the sequence of the mouse protein encoded by the normal rds gene. The differences between the two sequences can be attributed to species variation. Monoclonal antibodies were used with Western blot analysis to localize the wild-type mouse peripherin/rds protein to isolated mouse rod outer segments and to show that it, like bovine peripherin, exists as two subunits linked by one or more disulfide bonds. The relative amounts of peripherin/rds protein and rhodopsin in retinal extracts of normal and rds mutant mice were also compared. Identification of peripherin as the protein encoded by the normal rds gene and its localization to membranes of rod outer segments will serve as a basis for studies directed toward defining the role of this protein in the morphogenesis and maintenance of the outer segment and toward understanding the mechanism by which the rds mutation causes retinal degeneration.

Amino Acid Sequence↗
PubMed1995

NF1-L is the DNA-binding component of the protein complex at the peripherin 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 stimulates PC12 cells to differentiate into neurons. We have defined a negative regulatory element (NRE) that has a functional role in repressing peripherin expression in undifferentiate and nonneuronal cells. Nerve growth factor-induced derepression of peripherin gene expression is associated with alterations in proteins binding to a GC-rich DNA sequence in the NRE as detected by the DNA electrophoretic mobility shift assay (EMSA). We have utilized DNA affinity chromatography to purify from rat liver a 33-kDa DNA-binding protein that specifically recognizes the NRE. Microsequencing reveals identity with NF1-L, a member of the CTF/NF-1 transcription factor family. This protein forms a single complex when incubated with the NRE probe using EMSA analysis. The more slowly migrating complexes characteristic of crude undifferentiated PC12 cell extract are reconstituted by mixing the purified protein with the flow-through from the DNA affinity column, thereby demonstrating that protein-protein interactions are involved in complex formation. Supershift experiments incubating anti-CTF-1 antibody with undifferentiated PC12 cell extract prior to EMSA analysis confirm that NF1-L, or a closely related family member, is the DNA-binding protein component of the multiprotein complex at the NRE.

Amino Acid Sequence↗
PubMed2004

A novel tetraspanin fusion protein, peripherin-2, requires a region upstream of the fusion domain for activity.

Peripherin-2 (also known as peripherin/rds), a photoreceptor specific tetraspanin protein, is required to maintain normal cell structure through its role in renewal processes requiring membrane fusion. It is the first tetraspanin fusogen and has been shown to directly mediate fusion between disk membranes and opposing membranes to maintain the highly ordered structure of rod outer segments. Localized to the C terminus of human, bovine, and murine peripherin-2 is an amphiphilic fusion peptide domain (residues 312-326) and a highly conserved region upstream of this domain that we hypothesize is essential for fusogenic function. Our previous studies indicated that substitution of a threonine for a proline at position 296 within this highly conserved region enhanced fusion activity. In this study we wanted to determine whether this proline is essential with the introduction of three additional substitutions of proline with alanine, leucine, and glutamic acid. Wild type, P296T, P296A, P296L, and P296E mutants of peripherin-2 were expressed as His6-tagged full-length proteins in Madin-Darby canine kidney (MDCK) cells. All of the proteins were localized to intracellular membranes and detected as 42-kDa monomers by Western blot analysis. The wild type, P296A, and P296L assembled into core tetramers; in contrast the P296T and P296E formed higher order oligomers. Fusogenic activity of full-length protein expressed in MDCK membranes and purified protein reconstituted in model membrane liposomes was determined using fluorescence quenching techniques. Fusion activity was decreased in the P296L, P296A, and P296E mutants both in endogenous MDCK membranes and in model liposomes. Collectively, these results suggest that the proline at position 296 is necessary for optimal function.

Amino Acid Sequence↗
PubMed2006

Peripherin as a marker for degeneration of spiral ganglion neurons after aminoglycoside ototoxicity.

CONCLUSION: Our data show that temporary appearance of atypical type 1 neurons, like type 3 neurons, might be another degenerating form of spiral ganglion neurons (SGNs); peripherin might be a marker of degenerating neurons. OBJECTIVES: Further morphological and biochemical studies on surviving SGNs after loss of hair cells might offer clues for preventing their degeneration. MATERIALS AND METHODS: We observed the ultrastructural features of surviving SGNs and analyzed the peripherin immunoreactivity at 4, 10, or 20 weeks after systemic injection of neomycin in rats. RESULTS: Type 3 neurons, similar to type 1 neurons but unmyelinated, appeared in the spiral ganglion by 4-week survival, and showed a survival advantage in remaining SGNs by longer surviving periods. We observed neurons packed with dense intermediate filament and with multiple layers of dense myelin sheath (atypical type 1 neurons) in the degenerating neurons. Atypical type 1 neurons were observed among the degenerating neurons in the 4- and 10-week survival groups, but disappeared in longer surviving animals. By means of immunohistochemistry, only smaller SGNs of normal rats were strongly stained by anti-peripherin antibody, whereas increased immunoreactivity was observed in both large and small remaining neurons after neomycin treatment, especially in 10- and 20-week survival animals.

Animals↗
PubMed1993

Peripherin expression in hippocampal neurons induced by muscle soluble factor(s).

Previous studies have shown that neuronal cells in culture can switch neurotransmitters when grown in the presence of different target cells. To examine whether this plasticity extends to structural proteins, we cocultured hippocampal neurons and pituitary-derived neuroendocrine (AtT20) cells with astrocytes, kidney epithelial cells, or skeletal muscle cells. As a marker of phenotypic change we used the cytoskeletal protein peripherin, a type III intermediate filament (IF) subunit which is not expressed in hippocampal neurons and AtT20 cells. We show here that soluble factor(s) secreted specifically from skeletal muscle cells can induce the expression and de novo assembly of peripherin in a subset of post-mitotic neurons. We further demonstrate that one of these factors is the Leukemia Inhibitory Factor/Cholinergic Neuronal Differentiation Factor. The environmentally regulated expression of peripherin implies a remarkable degree of plasticity in the cytoskeletal organization of postmitotic CNS cells and provides a noninvasive model system to examine the de novo assembly of IF proteins under in vivo conditions.

Animals↗
PubMed1994

Identification of a locus, distinct from RDS-peripherin, for autosomal recessive retinitis pigmentosa on chromosome 6p.

We performed a genomic search for linkage to autosomal recessive retinitis pigmentosa in a large pedigree obtained from the Dominican Republic using microsatellite markers. Regions of the genome known to contain genes for retinitis pigmentosa were preferentially tested. One of these regions, on chromosome 6p, which contains the gene for peripherin, gave positive lod scores. Use of a mononucleotide repeat polymorphism in the peripherin gene excluded this locus. Two- and multi-point analyses suggest that the most likely location for the disease gene is near D6S291, which is located approximately 20 centimorgans telomeric from peripherin.

Chromosomes, Human, Pair 6↗