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U Suter

Publications and source records attributed to U Suter.

At least 55 records · Page 3Linked to original sources
PubMed1998

Many facets of the peripheral myelin protein PMP22 in myelination and disease.

Peripheral myelin protein 22 (PMP22) is a small, hydrophobic glycoprotein, which is most prominently expressed by Schwann cells as a component of compact myelin of the peripheral nervous system (PNS). Recent progress in molecular genetics revealed that mutations affecting the PMP22 gene including duplications, deletions, and point mutations are responsible for the most common forms of hereditary peripheral neuropathies including Charcot-Marie-Tooth disease type 1A (CMT1A), hereditary neuropathy with liability to pressure palsies (HNPP), and a subtype of Dejerine-Sottas Syndrome (DSS). Functionally, PMP22 is involved in correct myelination during development of peripheral nerves, the stability of myelin, and the maintenance of axons. While most of these functions relate to a role of PMP22 as a structural component of myelin, PMP22 has also been proposed as a regulator of Schwann cell proliferation and differentiation. In this review, we will discuss our current knowledge of PMP22 and its related proteins in the normal organism as well as in disease. In particular, we will focus on how the function of PMP22 and its regulation may be relevant to particular disease mechanisms.

Animals↗
PubMed1998

Neural membrane protein 35 (NMP35): a novel member of a gene family which is highly expressed in the adult nervous system.

We have identified and isolated a cDNA that codes for the novel protein NMP35 (neural membrane protein 35) using RNA arbitrarily primed PCR (RAP-PCR) for differential display in the developing rat sciatic nerve. NMP35 is predominantly found in the adult nervous system where both transcripts and protein are strongly upregulated during postnatal development. In situ hybridization studies show that NMP35 mRNA is widely distributed in the brain and spinal cord with a neuronal expression pattern. Database comparisons reveal that NMP35 shares significant homologies with the rat glutamate-binding protein (GBP), the Drosophila NMDARA1, and two orphan C. elegans genes. Comparative analysis of NMP35 and GBP expression indicates that they are similarly regulated during development and display regionally overlapping cellular patterns. We conclude that NMP35 and GBP are members of a gene family which is likely to play a role in the development and the maintenance of the nervous system.

Age Factors↗
PubMed1998

The glycoprotein P0 in peripheral gliogenesis.

Recent data show that during development protein zero, P0, the most abundant peripheral nerve myelin protein, is detecable long before myelination. In particular, the expression of P0 in a fraction of migrating neural crest reveals progenitor cell heterogeneity in the developing PNS. Here we review the regulation and potential function of P0 during peripheral gliogenesis.

Animals↗
PubMed1998

Progesterone stimulates the activity of the promoters of peripheral myelin protein-22 and protein zero genes in Schwann cells.

To understand better the mechanisms by which progesterone (PROG) promotes myelination in the PNS, cultured rat Schwann cells were transiently transfected with reporter constructs in which luciferase expression was controlled by the promoter region of either the peripheral myelin protein-22 (PMP22) or the protein zero (P0) genes. PROG stimulated the P0 promoter and promoter 1, but not promoter 2, of PMP22. The effect of PROG was specific, as estradiol and testosterone only weakly activated promoters. Dose-response curves for stimulation of both promoter constructs by PROG were biphasic. RU486, a PROG antagonist, did not abolish the effect of PROG, but stimulated promoter activities by itself. In the human carcinoma cell line T47D expressing high levels of PROG receptor, PROG did not stimulate the P0 and PMP22 promoters, whereas the promoter region of the mouse mammary tumor virus was fully activated. Thus, the activation by PROG of promoter activity of two peripheral myelin protein genes is Schwann-cell specific.

Animals↗
PubMed1997

Neurons promote the translocation of peripheral myelin protein 22 into myelin.

Schwann cells express low levels of myelin proteins in the absence of neurons. When Schwann cells and neurons are cultured together the production of myelin proteins is elevated, and myelin is formed. For peripheral myelin protein 22 (PMP22), the exact amount of protein produced is critical, because peripheral neuropathies result from its underexpression or overexpression. In this study we examined the effect of neurons on Schwann cell PMP22 production in culture and in peripheral nerve using metabolic labeling and pulse-chase studies as well as immunocytochemistry. Most of the newly synthesized PMP22 in Schwann cells is rapidly degraded in the endoplasmic reticulum. Only a small proportion of the total PMP22 acquires complex glycosylation and accumulates in the Golgi compartment. This material is translocated to the Schwann cell membrane in detectable amounts only when axonal contact and myelination occur. Myelination does not, however, alter the rapid turnover of PMP22 in Schwann cells. PMP22 may therefore be a unique myelin protein in that axonal contact promotes its insertion into the Schwann cell membrane and myelin without altering its rapid turnover rate within the cell.

Animals↗
PubMed1997

Analysis of compound heterozygous mice reveals that the Trembler mutation can behave as a gain-of-function allele.

The most common form of Charcot-Marie-Tooth disease, CMT1A, is correlated with a 1.5 megabase duplication on chromosome 17p.11.2 containing the peripheral myelin protein 22 (PMP22) gene. Deletion of the same region is associated with a second inherited neural disorder, the hereditary neuropathy with liability to pressure palsies (HNPP). Moreover, several distinct point mutations within the PMP22 coding region are associated with CMT1A and Dejerine-Sottas Syndrome in humans and the Trembler (Tr) and Trembler-J phenotypes in mice. Heterozygous Tr mutants (Tr/+) display severe hypomyelination of peripheral nerve fibers while heterozygous pmp22 knockout mice (pmp22+/0) are characterized by focal hypermyelination. These findings suggest that the Tr mutation does not generate a pmp22 null allele but rather produces its deleterious effects by either a dominant-negative or gain-of-function mechanism. To address this question in detail, we have compared various combinations of pmp22 alleles including Tr/+, Tr/Tr, Tr/0, pmp22+/0, and pmp22(0/0) mice with respect to the resulting myelin abnormalities. The combined analysis of these mutants demonstrates that the Tr allele can act as a true gain-of-function mutation in both, the heterozygous state on a null background (Tr/0) as well as in homozygous Tr animals (Tr/Tr). Furthermore, increasing the relative Tr gene dosage correlates with more pronounced myelin deficiencies and decreased levels of MBP and P0 in 18-day-old mice.

Alleles↗
PubMed1997

Structural abnormalities and deficient maintenance of peripheral nerve myelin in mice lacking the gap junction protein connexin 32.

Mutations affecting the connexin 32 (Cx32) gene are associated with the X-linked form of the hereditary peripheral neuropathy Charcot-Marie-Tooth disease (CMTX). We show that Cx32-deficient mice develop a late-onset progressive peripheral neuropathy with abnormalities comparable to those associated with CMTX, thus providing proof of the critical role of Cx32 in the maintenance of peripheral nerve myelin and an animal model for CMTX. Frequently observed features include abnormally thin myelin sheaths, cellular onion bulb formation reflecting myelin degeneration-induced Schwann cell proliferation, and enlarged periaxonal collars while nerve conductance properties are altered only slightly. These observations are consistent with earlier hypotheses suggesting a function of Cx32 as a channel-forming protein that facilitates the communication between the abaxonal and adaxonal aspects of Schwann cell cytoplasm.

Afferent Pathways↗
PubMed1997

Heterozygous peripheral myelin protein 22-deficient mice are affected by a progressive demyelinating tomaculous neuropathy.

Hereditary neuropathy with liability to pressure palsy (HNPP) is associated with a heterozygous 1.5 megabase deletion on chromosome 17 that includes the peripheral myelin protein (PMP) gene PMP22. We show that heterozygous PMP22 knock-out mice, which carry only one functional pmp22 allele and thus genetically mimic HNPP closely, display similar morphological and electrophysiological features as observed in HNPP nerves. As reported previously, focal hypermyelinating structures called tomacula, the pathological hallmarks of HNPP, develop progressively in young PMP22(+/0) mice. By following the fate of tomacula during aging, we demonstrate now that these mutant animals are also interesting models for examining HNPP disease mechanisms. Subtle electrophysiological abnormalities are detected in PMP22(+/0) mice >1 year old, and a significant number of abnormally swollen and degenerating tomacula are present. Thinly myelinated axons and supernumerary Schwann cells forming onion bulbs as fingerprints of repeated cycles of demyelination and remyelination are also encountered frequently. Quantitative analyses using electron microscopy on cross sections and light microscopy on single teased nerve fibers suggest that tomacula are intrinsically unstable structures that are prone to degeneration; however, the severity of morphological and electrophysiological abnormalities in PMP22(+/0) mice is variable. These combined findings are reminiscent of the disease progression in HNPP and offer a possible explanation about why some HNPP patients develop a chronic motor and sensory neuropathy later in life that resembles demyelinating forms of Charcot-Marie-Tooth disease by both morphological and clinical criteria.

Aging↗
PubMed1997

Myelin and lymphocyte protein (MAL/MVP17/VIP17) and plasmolipin are members of an extended gene family.

An increasing number of four-transmembrane proteins has been found to be associated with CNS and PNS myelin. Some of these proteins play crucial roles in the development and maintenance of the nervous system. In the CNS, proteolipid protein (PLP) is mutated in the myelin disorder Pelizaeus-Merzbacher disease and in spastic paraplegia, while in the PNS, peripheral myelin protein 22 (PMP22) and connexin32 (C x 32) are culprit genes in the most frequent forms of hereditary peripheral neuropathies. Myelin and lymphocyte protein (MAL; also called MVP17 or VIP17) and plasmolipin are additional tetraspan proteins that are highly expressed by myelinating glial cells. However, little is known about the role of these proteins in the nervous system. As a prerequisite for functional genetic approaches in the mouse, we have isolated and characterized a mouse MAL cDNA and the corresponding structural MAL gene. Computer-aided analysis and database searches revealed that MAL belongs to a larger gene family which also includes plasmolipin, BENE and the expressed sequence tag (EST) H09290. While the overall amino acid sequence identities between mouse MAL and the related proteins are relatively low (29-37%), the conserved motif -[Q/Y-G-W-V-M-F/Y-V]- which is found at the junction of the first extracellular loop and the second membrane-associated domain serves as a fingerprint for the MAL protein family. Expression analysis of the members of the MAL gene family indicates widespread expression in various tissues, suggesting a common role of these proteins in cell biology.

Amino Acid Sequence↗
PubMed1997

Myelin: keeping nerves well wrapped up.

The recently determined structure of protein zero, P0, the most abundant peripheral nerve myelin protein, provides new insights into the molecular structure of myelin and potential disease mechanisms in hereditary peripheral neuropathies.

Animals↗
PubMed1997

Aberrant protein trafficking in Trembler suggests a disease mechanism for hereditary human peripheral neuropathies.

The naturally occurring mouse mutant Trembler (Tr) represents an animal model for inherited human neuropathies caused by point mutations affecting peripheral myelin protein 22 (PMP22). We describe the likely pathogenic cellular mechanism underlying the observed myelin deficiency. In Tr/+ animals, PMP22 immunoreactivity was found not only in compact myelin but also abundantly in the cytoplasm of Schwann cells. Based on these observations, the biosynthesis of wildtype and Tr protein was examined in transfected cells. While wildtype PMP22 was readily transported to the plasma membrane, Tr protein was localized mainly in the endoplasmic reticulum. Coexpression revealed a dominant effect of Tr on protein trafficking of wildtype PMP22. In agreement with the findings in vitro, Tr protein was not detectable in myelin of Tr/0 mice.

Animals↗
PubMed1997

Advances in Charcot-Marie-Tooth disease research: cellular function of CMT-related proteins, transgenic animal models, and pathomechanisms. The European CMT Consortium.

The First Workshop of the European Consortium on Charcot-Marie-Tooth (CMT) disease brought together neuroscientists, molecular and cell biologists, neuropathologists, neurologists, and geneticists with a common interest in the understanding of the fundamental mechanisms that underlie the pathogenesis of CMT. The interdisciplinary group of 25 expert scientists discussed recent advances in (i) molecular genetics and histopathology of CMT, (ii) development of suitable animal models, (iii) understanding of the cellular function of CMT-related proteins, and (iv) studies using nerve biopsies from CMT patients. In this minireview, we summarize the key findings presented and discuss their impact on CMT research.

Animals↗
PubMed1996

The regulated secretion and vectorial targeting of neurotrophins in neuroendocrine and epithelial cells.

The varied roles that neurotrophins play in the development and activity-dependent plasticity of the nervous system presumably require that the sites and quantity of neurotrophin release be precisely regulated. As a step toward understanding how different neurotrophins are sorted and secreted by neurons, we expressed nerve growth factor (NGF), brain-derived neurotrophic factor, and neurotrophin-3 in cell lines used as models for neuronal protein sorting. All three neurotrophins were secreted by a regulated pathway in transfected AtT-20 and PC12 neuroendocrine cells, with a 3-6-fold increase in neurotrophin release in response to 8-bromo-cAMP or depolarization, respectively. To determine if the propeptide directs the intracellular sorting of mature NGF, we examined mutants in which regions spanning the propeptide were deleted. These mutants underwent regulated release in every case in which expression could be detected. Similarly, NGF sorting was not significantly altered by mutations which specifically abolished N-glycosylation or proteolytic processing sites within the NGF precursor. Finally, we found that all three neurotrophins were secreted 65-75% basolaterally by polarized Madin-Darby canine kidney epithelial cells. These findings suggest that the determinants of regulated neurotrophin secretion lie within the mature neurotrophin moiety and that NGF, brain-derived neurotrophic factor, and neurotrophin-3 are likely to be sorted similarly and released in a regulated manner by neurons.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

Epithelial membrane protein-2 and epithelial membrane protein-3: two novel members of the peripheral myelin protein 22 gene family.

Peripheral myelin protein 22 (PMP22) is expressed by Schwann cells in the peripheral nervous system (PNS), and mutations affecting the PMP22 gene are associated with hereditary motor and sensory neuropathies. We have previously defined the PMP22/EMP/MP20 gene family by characterizing the PMP22-related epithelial membrane protein-1 (EMP-1). We now report the identification of two additional members of the same family, epithelial membrane protein-2 and epithelial membrane protein-3 (EMP-2 and EMP-3). Both cDNA-predicted polypeptides share approx. 40% aa identity with PMP22. In human, EMP-2 and EMP-3 mRNA transcripts are found in most tissues with an expression pattern partially overlapping that of PMP22 and EMP-1. EMP-2 is most prominently expressed in the adult ovary, heart, lung and intestine and in fetal lung. The levels of EMP-3 transcripts are highest in peripheral blood leukocytes, ovary, intestine and various embryonic tissues. In contrast to PMP22 and EMP-1, EMP-2 and EMP-3 expression is detectable in the liver. In vitro transcription-translation generates EMP-2 and EMP-3 polypeptides of 18 kDa which is in agreement with their predicted sizes. Since PMP22 has been implicated in the regulation of cell proliferation and apoptosis, it appears likely that these novel members of the PMP22/EMP/MP20 protein family are also involved in similar regulatory processes in a variety of tissues.

Adult↗
PubMed1996

Identification and characterization of a cDNA and the structural gene encoding the mouse epithelial membrane protein-1.

The PMP22/EMP/MP20 gene family includes four closely related proteins, peripheral myelin protein-22 (PMP22), epithelial membrane protein-1 (EMP-1), epithelial membrane protein-2 (EMP-2), and epithelial membrane protein-3 (EMP-3), which share amino acid identities ranging from 33 to 43%. In addition, the lens-specific membrane protein MP20 represents a more distant relative. Functionally, this family of proteins is likely to play important roles in the control of cell proliferation, cell differentiation, and cell death. In particular, mutations affecting the PMP22 gene are responsible for various hereditary peripheral neuropathies in humans and mice. We report the isolation and characterization of a mouse EMP-1 cDNA and the corresponding emp-1 gene. Mouse EMP-1 displays 93% amino acid identity to rat EMP-1 and 39% identity to mouse PMP22. The cDNA-predicted EMP-1 protein contains four putative membrane-associated domains and can be N-linked glycosylated in vitro. EMP-1 is encoded by a single-copy gene with the positions of introns exactly conserved between emp-1 and PMP22, corroborating the hypothesis that both genes belong to the same family. Computer-predicted structural domains of EMP-1 are partially mirrored by the exon/intron structure of emp-1. Most interestingly, exon 4, which covers the potential second transmembrane domain, a small intracellular loop, and half of the third transmembrane domain, encodes the most highly conserved regions between the EMP-1 and PMP22 proteins and is also remarkably conserved in the MP20 gene, indicating some shared functional significance for this module in the PMP22/EMP/MP20 family.

Amino Acid Sequence↗