Animal Models of Genetic Disorders of Myelin

Hogan, Edward L.; Greenfield, Seymour

doi:10.1007/978-1-4757-1830-0_14

Cited by 138 publications

(108 citation statements)

References 110 publications

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“…The few myelinated axons contained reduced lamellae that failed to form compact myelin. This is consistent with previous biochemical studies indicating that the qk v /qk v mutant produces only 5-10% of the myelin in normal animals (Singh et al, 1971;Hogan and Greenfield, 1984). In contrast, the qk v /wt littermates formed compact myelin on Ͼ80% of axons in the corpus callosum and optic nerve (Fig.…”

Section: Resultssupporting

confidence: 92%

“…Homozygous qk v mutants suffer from diminished expression of myelin structural proteins and severe hypomyelination (Sidman et al, 1964;Hogan and Greenfield, 1984;Hardy, 1998). The qk v mutation deletes an enhancer of the qkI gene and causes diminished qkI transcription specifically in myelin-producing cells (Hardy et al, 1996;Lu et al, 2003), which is postulated as the cause for dysmyelination (Hardy, 1998;McInnes and Lauriat, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Rescuing qk^vDysmyelination by a Single Isoform of the Selective RNA-Binding Protein QKI

Zhao¹,

Tian²,

Xia³

et al. 2006

J. Neurosci.

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Alternative splicing of the qkI transcript generates multiple isoforms of the selective RNA-binding protein QKI, which play key roles in controlling the homeostasis of their mRNA targets. QKI deficiency in oligodendrocytes of homozygous quakingviable (qk v /qk v ) mutant mice results in severe hypomyelination, indicating the essential function of QKI in myelinogenesis. However, the molecular mechanisms by which QKI controls myelination remain elusive. We report here that QKI-6 is the most abundant isoform in brain and is preferentially reduced in the qk v /qk v mutant during normal myelinogenesis. To test whether QKI-6 is the predominant isoform responsible for advancing CNS myelination, we developed transgenic mice that express Flag-QKI-6 specifically in the oligodendroglia lineage, driven by the proteolipid protein (PLP) promoter. When introduced into the qk v /qk v mutant, the QKI-6 transgene rescues the severe tremor and hypomyelination phenotype. Electron microscopic studies further revealed that the Flag-QKI-6 transgene is sufficient for restoring compact myelin formation with normal lamellar periodicity and thickness. Interestingly, Flag-QKI-6 preferentially associates with the mRNA encoding the myelin basic protein (MBP) and rescues MBP expression from the beginning of myelinogenesis. In contrast, Flag-QKI-6 binds the PLP mRNA with lower efficiency and has a minimal impact on PLP expression until much later, when the expression level of QKI-6 in the transgenic animal significantly exceeds what is needed for normal myelination. Together, our results demonstrate that QKI-6 is the major isoform responsible for CNS myelination, which preferentially promotes MBP expression in oligodendrocytes.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Rescuing qk^vDysmyelination by a Single Isoform of the Selective RNA-Binding Protein QKI

Zhao¹,

Tian²,

Xia³

et al. 2006

J. Neurosci.

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“…The quaking genes from X. laevis, D. melanogaster, and mice are involved in a variety of processes, such as myelination, embryogenesis, muscle development, and notochord development (2,7,16,20,23,33,34,42,45). The pleiotropic roles and the high level of conservation of this gene suggest a general function for Qk1 in cellular processes.…”

Section: Discussionmentioning

confidence: 99%

“…This might interfere with Qk1 function and lead to the myelin dysregulation observed in the central nervous systems of these animals. The quaking viable mice have been extensively studied (20), and several defects in RNA metabolism have been observed. Alterations in the levels of alternatively spliced RNAs and in the processing and/or turnover of the mRNA transcripts encoding myelin-associated glycoprotein, myelin basic protein, and proteolipid protein have been demonstrated (4,6,13,19).…”

Section: Discussionmentioning

confidence: 99%

Structure-Function Analysis of Qk1: a Lethal Point Mutation in Mouse quaking Prevents Homodimerization

Chen

Richard

1998

Molecular and Cellular Biology

112

131

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Qk1 is a member of the KH domain family of proteins that includes Sam68, GRP33, GLD-1, SF1, and Who/How. These family members are RNA binding proteins that contain an extended KH domain embedded in a larger domain called the GSG (for GRP33-Sam68-GLD-1) domain. An ethylnitrosourea-induced point mutation in the Qk1 GSG domain alters glutamic acid 48 to a glycine and is known to be embryonically lethal in mice. The function of Qk1 and the GSG domain as well as the reason for the lethality are unknown. Here we demonstrate that the Qk1 GSG domain mediates RNA binding and Qk1 self-association. By using in situ chemical cross-linking studies, we showed that the Qk1 proteins exist as homodimers in vivo. The Qk1 self-association region was mapped to amino acids 18 to 57, a region predicted to form coiled coils. Alteration of glutamic acid 48 to glycine (E¦G) in the Qk1 GSG domain (producing protein Qk1:E¦G) abolishes self-association but has no effect on the RNA binding activity. The expression of Qk1 or Qk1:E¦G in NIH 3T3 cells induces cell death by apoptosis. Approximately 90% of the remaining transfected cells are apoptotic 48 h after transfection. Qk1:E¦G was consistently more potent at inducing apoptosis than was wild-type Qk1. These results suggest that the mouse quaking lethality (E¦G) occurs due to the absence of Qk1 self-association mediated by the GSG domain.

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“…The quaking viable (qk v ) mice have been studied for more than thirty years and represent an animal model for dysmyelination (Hogan and Greenfield 1984). Ten days after birth these animals develop a rapid tremor that is especially pronounced in the hind limbs (Hogan and Greenfield 1984).…”

mentioning

confidence: 99%

Nuclear translocation controlled by alternatively spliced isoforms inactivates the QUAKING apoptotic inducer

Pilotte¹,

Larocque²,

Richard³

2001

Genes Dev.

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The quaking viable mice have myelination defects and develop a characteristic tremor 10 d after birth. The quaking gene encodes at least five alternatively spliced QUAKING (QKI) isoforms that differ in their C-terminal 8-30-amino-acid sequence. The reason for the existence of the different QKI isoforms and their function are unknown. Here we show that only one QKI isoform, QKI-7, can induce apoptosis in fibroblasts and primary rat oligodendrocytes. Heterodimerization of the QKI isoforms results in the nuclear translocation of QKI-7 and the suppression of apoptosis. The unique C-terminal 14 amino acids of QKI-7 confers the ability to induce apoptosis to heterologous proteins such as the green fluorescent protein and a QKI-related protein, Caenorhabditis elegans GLD-1. Thus, the unique C-terminal sequences of QKI-7 may function as a life-or-death 'sensor' that monitors the balance between the alternatively spliced QKI isoforms. Moreover, our findings suggest that nuclear translocation is a novel mechanism of inactivating apoptotic inducers. Apoptosis, or programmed cell death, is a physiological process characterized by a cascade of events culminating in the destruction of the cell. There are numerous protein families that have been shown to induce apoptosis including the TNF

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Animal Models of Genetic Disorders of Myelin

Cited by 138 publications

References 110 publications

Rescuing qk^vDysmyelination by a Single Isoform of the Selective RNA-Binding Protein QKI

Rescuing qk^vDysmyelination by a Single Isoform of the Selective RNA-Binding Protein QKI

Structure-Function Analysis of Qk1: a Lethal Point Mutation in Mouse quaking Prevents Homodimerization

Nuclear translocation controlled by alternatively spliced isoforms inactivates the QUAKING apoptotic inducer

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Animal Models of Genetic Disorders of Myelin

Cited by 138 publications

References 110 publications

Rescuing qkvDysmyelination by a Single Isoform of the Selective RNA-Binding Protein QKI

Rescuing qkvDysmyelination by a Single Isoform of the Selective RNA-Binding Protein QKI

Structure-Function Analysis of Qk1: a Lethal Point Mutation in Mouse quaking Prevents Homodimerization

Nuclear translocation controlled by alternatively spliced isoforms inactivates the QUAKING apoptotic inducer

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Rescuing qk^vDysmyelination by a Single Isoform of the Selective RNA-Binding Protein QKI

Rescuing qk^vDysmyelination by a Single Isoform of the Selective RNA-Binding Protein QKI