Hypermyelination and demyelinating peripheral neuropathy in Pmp22-deficient mice

Adlkofer, Katrin; Martini, Rudolf; Aguzzi, Adriano; Zielasek, Jürgen; Toyka, Klaus V.; Suter, Ueli

doi:10.1038/ng1195-274

Cited by 346 publications

(338 citation statements)

References 45 publications

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“…However, it is interesting to note that PMP22 is likely to function as an adhesion molecule. 12,59 Along these lines, it is interesting to note that in the affected tissues of zebrafish embryos, perp-deficient cells display alterations in cell shape coincident with or even prior to apparent signs of apoptosis (Figure 8). Proper cell adhesion can be essential for cell survival 60 and differentiation.…”

Section: Discussionmentioning

confidence: 94%

“…PMP22 is a major myelin component of Schwann cells, and both gain and loss of PMP22 function leads to peripheral neuropathies in mouse and man. Specifically, the hereditary neuropathy with liability to pressure palsies (HNPP) is caused by a deletion of the PMP22 gene, 11,12 while the demyelinating hereditary motor sensory neuropathy Charcot-Marie-Tooth disease type 1A (CMT1A) is due to a heterozygous duplication of the same DNA segment. 13 In rare cases, CMT1A can also be caused by point mutations in the PMP22 gene, and in mice, similar mutations are associated with the Trembler and Trembler-J phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Perp is required for tissue-specific cell survival during zebrafish development

2004

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The tumor suppressor p53 has two alternative effects, causing either cell cycle arrest or apoptosis. These different effects are supposed to be mediated by the transcriptional activation of different target genes. perp, encoding a transmembrane protein of the Pmp22 family, is a transcriptional p53 target exclusively upregulated in apoptotic cells. However, its role during normal development had remained largely unclear. Here, we report the isolation and characterization of a zebrafish perp homolog. Upon overexpression in early zebrafish embryos, perp induces apoptosis. In addition, it contributes to p53-dependent and UVinduced cell death. However, during normal zebrafish development, perp displays a p53-independent and spatially restricted expression in specific cell types and tissues. Antisensemediated loss of Perp function leads to increased apoptosis in perp-expressing cells of the developing skin and notochord. We conclude that, in contrast to its proapoptotic function in stressed cells, Perp plays an antiapoptotic role during normal zebrafish development to regulate tissue-specific cell survival. Cell Death and Differentiation (2005) Keywords: perp; p53; pmp22; apoptosis; cell survival; zebrafish; development Abbreviations: AO, acridine orange; BrdU, 5 0 Bromo-2 0 -desoxyuridine; DNp63, amino-terminally truncated isoform of p63; EST, expressed sequence tag; EVL, enveloping layer; hpf, hours postfertilization; mdm2, mouse double minute 2; MO, morpholino oligonucleotide; RT-PCR, polymerase chain reaction after reverse transcription of RNA; SDS-PAGE, sodiumdodecylsulfate polyacrylamide gel electrophoresis; TAp73, transactivating N-terminally full-length isoform of p73; TUNEL, terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling; UV, ultraviolet; 4 mm, four mismatch control

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Perp is required for tissue-specific cell survival during zebrafish development

2004

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“…Mice lacking PMP22 are born and develop normally until the second week of life when walking difficulties due to progressive weakness of the hindlimbs appear (Adlkofer et al 1995). A progressive peripheral neuropathy characterized by a delayed onset of myelination and the characteristic formation of paranodal and internodal tomacula, very prominent in 3-week-old mice, develops.…”

Section: Genetics Of Hmsnmentioning

confidence: 99%

Mouse genetics in cell biology

Mansuy¹,

Suter²

2000

Exp. Physiol.

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One of the most fascinating challenges in modern cell biology is the unravelling of the molecular mechanisms underlying the development and formation of functional organs, and the maintenance and regeneration of vertebrate tissues. In such processes, cell-cell interactions, mediated by direct contacts or secreted factors, and cell-extracellular matrix interactions are essential for the control of cell proliferation, migration, differentiation and death. These events are mediated by numerous molecular signals that have to be integrated within the cell to activate specific sets of regulatory factors responsible for correct spatial and temporal gene regulation. We are still far away from a complete understanding of these complex events at a molecular level but molecular genetic and genomic approaches have provided valuable tools and methodologies for the study of complex cellular functions in vivo. In particular, the development of reverse genetic methods such as transgene expression and gene targeting has allowed substantial progress in the understanding of the molecular mechanisms of cell-cell and cell-extracellular interactions. Although initially limited by a lack of spatial and temporal specificity, these approaches have recently undergone major developments partly overcoming these limitations, and have brought novel perspective into the application of genetic tools for the study of highly complex biological functions. To illustrate the power of genetic approaches in cell biology, we will describe in the first part of this review, several examples of mutant mice models that have allowed studies of developmental processes and neuron-glia interactions in the peripheral nervous system (PNS). The second part of the review will focus on recent advances of genetic approaches by describing the major methodologies, their latest developments and a few remarkable examples of their application in neurobiology and cancer research. Cell-cell and cell-extracellular matrix interactionsNeuronal and glial cell interactions in the nervous system Peripheral nerves are well suited to the study of the mechanisms of cell-cell interactions in organogenesis, a process in which cells determine the fate of their neighbours (Taylor & Suter, 1997;Jessen & Mirsky, 1999). This is exemplified in the process of myelination where two cell types, neurons and Schwann cells, exhibit a profound influence on each other. While axons regulate the proliferation and differentiation of Schwann cells, the latter are the main determinants of axon calibre and ion channel distribution. It has recently become clear that this cellular interdependence is not restricted to postnatal events, but that embryonic Schwann cell precursors and neurons also support each other for survival during critical periods of development. Furthermore, disturbance of the delicate balance between neuron and glia interactions by genetic manipulation has been revealed to be Genetic methodologies have provided powerful means for investigating the cellular and molecular mechanisms of ...

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“…Trembler mouse (Suter et al, 1992); hypomorph (Maycox et al, 1997); Pmp22 targeted mutagenesis (Adlkofer et al, 1995); transgenesis (Huxley et al, 1996;; inducible Pmp22 overexpression (Perea et al, 2001) Smith-Magenis Syndrome (SMS)…”

Section: Pmp22mentioning

confidence: 99%

“…Homozygous transgenic animals completely fail to elaborate myelin. To model HNPP, the Pmp22 gene was targeted (Adlkofer et al, 1995). Homozygous null mice develop a neuropathy similar to HNPP with very slow conduction velocities, while heterozygous mice show a less severe phenotype.…”

Section: Charcot-marie-tooth Disease -Human Hereditary Neuropathy Witmentioning

confidence: 99%

Animal models for human contiguous gene syndromes and other genomic disorders

2004

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Genomic disorders refer to a group of syndromes caused by DNA rearrangements, such as deletions and duplications, which result in an alteration of normal gene dosage. The chromosomal rearrangements are usually relatively small and often difficult to detect cytogenetically. In a subset of such conditions the rearrangements comprise multiple unrelated contiguous genes that are physically linked and thus have been referred to as contiguous gene syndromes (CGS). In general, each syndrome presents a complex clinical phenotype that has been attributed generally to dosage sensitive gene(s) present in the responsible chromosomal interval. A common mechanism for CGS resulting from interstitial deletion/duplication has recently been elucidated. The DNA rearrangements result from nonallelic homologous recombination (NAHR) utilizing flanking low-copy repeats (LCRs) as recombination substrates. The resulting rearrangements often involve the same genomic region, a common deletion or duplication, making it difficult to assign a specific phenotype or endophenotype to a single responsible gene. The human and mouse genome sequencing projects, in conjunction with the ability to engineer mouse chromosome rearrangements, have enabled the production of mouse models for CGS and genomic disorders. In this review we present an overview of different techniques utilized to generate mouse models for selected genomic disorders. These models foment novel insights into the specific genes that convey the phenotype by dosage and/or position effects and provide opportunities to explore therapeutic options.

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Hypermyelination and demyelinating peripheral neuropathy in Pmp22-deficient mice

Cited by 346 publications

References 45 publications

Perp is required for tissue-specific cell survival during zebrafish development

Perp is required for tissue-specific cell survival during zebrafish development

Mouse genetics in cell biology

Animal models for human contiguous gene syndromes and other genomic disorders

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