Long Lives for Homozygous Trembler Mutant Mice Despite Virtual Absence of Peripheral Nerve Myelin

Henry, Earl Webb; Sidman, Richard L.

doi:10.1126/science.3388045

Cited by 60 publications

(32 citation statements)

References 17 publications

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“…The phenotype of PMP22-transgenic animals is similar but not identical to that of Tr mice, which carry a point mutation in the pmp22 gene (Henry et al, 1983;Henry and Sidman, 1988). Severe hypomyelination and increased Schwann cell number are the main common morphological features, and prominent pockets of redundant basal laminae surrounding hypomyelinated axons have been described in both mouse mutants (Low, 1977).…”

Section: Consequences Of Pmp22 Overexpression and Comparison To Pmp22mentioning

confidence: 85%

Impaired Differentiation of Schwann Cells in Transgenic Mice with IncreasedPMP22Gene Dosage

Magyar¹,

Martini

Rülicke³

et al. 1996

J. Neurosci.

229

145

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An intrachromosomal duplication containing the PMP22 gene is associated with the human hereditary peripheral neuropathy Charcot-Marie-Tooth disease type 1A, and PMP22 overexpression as a consequence of increased PMP22 gene dosage has been suggested as causative event in this frequent disorder of peripheral nerves. We have generated transgenic mice that carry additional copies of the pmp22 gene to prove that increased PMP22 gene dosage is sufficient to cause PNS myelin deficiencies. Mice carrying approximately 16 and 30 copies of the pmp22 gene display a severe congenital hypomyelinating neuropathy as characterized by an almost complete lack of myelin and marked slowing of nerve conductions. Affected nerves contain an increased number of nonmyelinating Schwann cells, which do not form onion bulbs but align in association with axons. The mutant Schwann cells are characterized by a premyelination-like state as indicated by the expression of embryonic Schwann cell markers. Furthermore, continued Schwann cell proliferation is observed into adulthood. We hypothesize that Schwann cells are impaired in their differentiation into the myelinating phenotype, leading to a disorder comparable to severe cases of hereditary motor and sensory neuropathies. Our findings, combined with the analysis of heterozygous and homozygous PMP22-deficient mice, indicate that aberrant pmp22 gene copy numbers cause various forms of myelination defects.

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Section: Consequences Of Pmp22 Overexpression and Comparison To Pmp22mentioning

confidence: 85%

Impaired Differentiation of Schwann Cells in Transgenic Mice with IncreasedPMP22Gene Dosage

Magyar¹,

Martini

Rülicke³

et al. 1996

J. Neurosci.

229

145

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“…We demonstrate that ablation of Schwann and BC cells or inactivation of Krox20 results in an invasion of dorsal and ventral nerve roots by astrocytes and oligodendrocytes, followed by myelination of their axons by oligodendrocytes. This phenotype is not observed with the Trembler J mutation, which blocks PNS myelination, but not Krox20 expression (Henry and Sidman, 1988;Giambonini-Brugnoli et al, 2005), suggesting that maintenance of the CNS/PNS boundary involves a Krox20 function that can be separated from myelination control. Furthermore, we also observed the presence of oligodendrocytes and astrocytes in the periphery in a human case of peripheral amyelinating neuropathy associated with absence of the KROX20 protein.…”

Section: Introductionmentioning

confidence: 90%

“…To differentiate between these two possibilities, we made use of another mutant, Trembler J/J , which carries a missense mutation in the PMP22 coding sequence (Sidman et al, 1979). PMP22 is a transmembrane protein involved in peripheral myelin compaction, and this mutation completely prevents the formation of myelin (Henry and Sidman, 1988), as shown by electron microscopy (Fig. 3F) and the absence of P0 expression (Fig.…”

Section: Absence Of Central-type Glia In Tremblermentioning

confidence: 99%

CNS/PNS Boundary Transgression by Central Glia in the Absence of Schwann Cells or Krox20/Egr2 Function

Coulpier¹,

Decker²,

Funalot³

et al. 2010

J. Neurosci.

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“…That at least part of the Tr J phenotype is unique to this mutation and is not simply a result of general myelin loss is suggested by comparison to homozygous Tr mice. In contrast to Tr J /Tr J , Tr/Tr mice live a normal life span even with a virtual absence of peripheral myelin (Henry and Sidman, 1988). In Tr/ϩ mice, the progression of the disease is more rapid than in Tr J /ϩ mice, leading to prominent histological abnormalities (e.g., "onion bulb" formation) in aged animals .…”

Section: Abstract: Peripheral Myelin Protein 22; Schwann Cells; Perimentioning

confidence: 98%

Upregulation of the Endosomal-Lysosomal Pathway in the Trembler-J Neuropathy

1997

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A nonconservative leucine to proline mutation in peripheral myelin protein 22 (PMP22) causes the Trembler-J (Tr J ) neuropathy in mice and humans. The expression levels and localization of the PMP22 protein in the Tr J mouse have not been previously determined. The aim of our studies was to reevaluate the extent of myelin deficit in genotyped heterozygous and homozygous animals and to examine how the Tr J mutation alters the normal in vivo post-translational processing of PMP22. Morphological studies show evidence for primary dysmyelination and myelin instability in affected animals. As expected, Western blot analysis indicates that in adult heterozygous Tr J animals, the level of PMP22 is markedly decreased, similar to myelin basic protein and protein zero, whereas myelin-associated glycoprotein is largely unaffected. The decrease in myelin protein expression is associated with an increase in lysosomal biogenesis, suggestive of augmented endocytosis or autophagy. Double-immunolabeling experiments show the accumulation of PMP22 in endosomal/lysosomal structures of Tr J Schwann cells, and chloroquine treatment of nerve segments indicates that the degradation of protein zero, PMP22, and myelin basic protein is augmented in Tr J nerves. These studies suggest that the Tr J mutation alters myelin stability and that the mutant protein is likely degraded via the lysosomal pathway. Key words: peripheral myelin protein 22; Schwann cells; peripheral nervous system; myelin; neuropathy; Trembler-J; endosomal-lysosomal pathway; protein processingThe Trembler (Tr) and Trembler-J (Tr J ) mice are animal models for the human hereditary neuropathy Charcot-Marie-Tooth (CMT) disease, a group of common (1/2500) (Skre, 1974) heterogeneous peripheral neuropathies. In mice, the semidominant and dominantly inherited mutations in the pmp22 gene result in the nonconservative leucine-to-proline (L16P) or glycine-toaspartic acid (G160D) replacements in the PMP22 protein in the Tr J or Tr mouse, respectively (Suter et al., 1992a,b). These mutations are believed to be responsible for the PNS deficits. The majority of human patients with CMT, however, do not have point mutations in the PMP22 gene, but instead harbor a submicroscopic chromosomal duplication on human chromosome 17p11.2-12, which encompasses the PMP22 gene (for review, see Suter and Snipes, 1995a). The similarity of the disease phenotypes, including disease progression, as well as the finding of the identical Tr J single point mutation in a severely affected CMT disease type 1A (CMT1A) family (Valentijn et al., 1992) substantiates the use of these mice as models of human disease and provide a system for elucidating the biology of the PMP22 protein.The ways in which pmp22 mutations perturb myelination are complex, particularly because the function of the PMP22 protein is unknown (for review, see Suter and Snipes, 1995b). Previous morphological studies of the Tr J mouse used the close linkage of the Tr J phenotype to the vestigial tail marker on mouse chromosome 11 to predict the ...

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Long Lives for Homozygous Trembler Mutant Mice Despite Virtual Absence of Peripheral Nerve Myelin

Cited by 60 publications

References 17 publications

Impaired Differentiation of Schwann Cells in Transgenic Mice with IncreasedPMP22Gene Dosage

Impaired Differentiation of Schwann Cells in Transgenic Mice with IncreasedPMP22Gene Dosage

CNS/PNS Boundary Transgression by Central Glia in the Absence of Schwann Cells or Krox20/Egr2 Function

Upregulation of the Endosomal-Lysosomal Pathway in the Trembler-J Neuropathy

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