Quaking*Shiverer Double-Mutant Mice Survive for at Least 100 Days with No CNS Myelin

Wolf, Merrill K.; Nunnari, John J.; Billings‐Gagliardi, Susan

doi:10.1159/000017415

Cited by 7 publications

(6 citation statements)

References 21 publications

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“…Data presented here and in the companion paper [36] indicate that juvenile-lethal Plp mutations are not fatal simply because the mice lack CNS myelin. The question now becomes: what does kill these mice?…”

Section: Possible Contribution Of An Inflammatory Process To the Jp-mmentioning

confidence: 58%

Evidence that CNS Hypomyelination Does Not Cause Death of Jimpy-msd Mutant Mice

et al. 1999

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Mice expressing three of the proteolipid protein (Plp) mutations in the mouse (jimpy, jimpy-msd, and jimpy-4J) all have a severe deficiency of CNS myelin and oligodendrocytes (OLs), and die sometime in their 4th postnatal week. The prevailing view has been that the animals’ shortened life span and lack of myelin are causally related. Here we describe the survival of jimpy-msd males for as long as postnatal day (P) 210. Although these spontaneously occurring longer-lived jimpy-msd males show a 2- to 8-fold increase in numbers of myelinated axons in many CNS regions, this does not protect them from a later but still premature death. Investigating the cause of premature death may reveal previously undiscovered properties of the myelin genes or the cells that express them, or perhaps additional unsuspected cellular responses that contribute to the disease. This study identifies small accumulations of inflammatory cells in the brain parenchyma of jimpy-msd mice as young as P14 and as old as P60, suggesting that the pathology of the disease produced by at least this Plp mutation may be far more complex than has been previously recognized.

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Section: Possible Contribution Of An Inflammatory Process To the Jp-mmentioning

confidence: 58%

Evidence that CNS Hypomyelination Does Not Cause Death of Jimpy-msd Mutant Mice

et al. 1999

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“…While hypomyelination is always detrimental, studies of mutant animals with different degrees of hypomyelination demonstrate the lack of a relationship between the extent of hypomyelination and premature death (Duncan et al, 1995). Notably, it has been shown that mutant mice completely lacking myelin can survive at least 100 days (Wolf et al, 1999). This demonstrates that the supportive role of oligodendrocytes is complex and likely extends beyond myelination.…”

Section: Discussionmentioning

confidence: 99%

Transplanted human glial-restricted progenitors can rescue the survival of dysmyelinated mice independent of the production of mature, compact myelin

Lyczek

Arnold

Zhang

et al. 2017

Experimental Neurology

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The therapeutic effect of glial progenitor transplantation in diseases of dysmyelination is currently attributed to the formation of new myelin. Using magnetic resonance imaging (MRI), we show that the therapeutic outcome in dysmyelinated shiverer mice is dependent on the extent of cell migration but not presence of mature and compact myelin. Human or mouse glial restricted progenitors (GRPs) were transplanted into rag2−/− shiverer mouse neonates and followed for over one year. Mouse GRPs produced mature myelin as detected with multi-parametric MRI, but showed limited migration without extended animal lifespan. In sharp contrast, human GRPs migrated extensively and significantly increased animal survival, but production of mature myelin did not occur until 46 weeks post-grafting. We conclude that human GRPs can extend the survival of transplanted shiverer mice prior to production of mature myelin, while mouse GRPs fail to extend animal survival despite early presence of mature myelin. This paradox suggests that transplanted GRPs provide therapeutic benefits through biological processes other than mature myelin capable to facilitate rapid conduction, challenging the current dogma of the role of myelin in the function of the central nervous system.

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“…The paucity of myelin is certainly a major factor contributing to behavioral deficits but is an incomplete explanation because certain rodents that have PLP mutations and virtually no CNS myelin have longer lifespans than some myelin-deficient rodents with reasonable numbers of myelinated fibers. 42 Oligodendrocyte death is a common finding in animals that overexpress native Plp or have point mutations, but the extent to which Olg death contributes to the animals' death is still unclear. 7,8 Induction of the unfolded protein response (UPR) occurs in COS-7 cells engineered to express PLP point mutations, 43 and accumulation of misfolded protein in the endoplasmic reticulum generally correlates with the decreased lifespan of these mutants.…”

Section: Discussionmentioning

confidence: 99%

The myelin proteolipid protein gene modulates apoptosis in neural and non-neural tissues

et al. 2004

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Mutations of the myelin proteolipid protein gene (Plp) are associated with excessive programmed cell death (PCD) of oligodendrocytes. We show for the first time that PLP is a molecule ubiquitously expressed in non-neural tissues during normal development, and that the level of native PLP modulates the level of PCD. We analyze three non-neural tissues, and show that native PLP is expressed in trophoblasts, spermatogonia, and cells of interdigital webbing. The non-neural cells that express high levels of native PLP also undergo PCD. The level of PLP expression modulates the level of PCD because mice that overexpress native PLP have increased PCD and mice deficient in PLP have decreased PCD. We show that overexpression of native PLP causes a dramatic acidification of extracellular fluid that, in turn, causes increased PCD. These studies show that the level of native PLP modulates the amount of PCD during normal development via a pH-dependent mechanism.

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Quaking*Shiverer Double-Mutant Mice Survive for at Least 100 Days with No CNS Myelin

Cited by 7 publications

References 21 publications

Evidence that CNS Hypomyelination Does Not Cause Death of Jimpy-msd Mutant Mice

Evidence that CNS Hypomyelination Does Not Cause Death of Jimpy-msd Mutant Mice

Transplanted human glial-restricted progenitors can rescue the survival of dysmyelinated mice independent of the production of mature, compact myelin

The myelin proteolipid protein gene modulates apoptosis in neural and non-neural tissues

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