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At least 145 records · Page 8Linked to original sources
PubMed2001

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

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.

3T3 Cells↗
PubMed1999

Quaking*shiverer double-mutant mice survive for at least 100 days with no CNS myelin.

Mice expressing mutations that produce CNS hypomyelination often die prematurely: the more severe the hypomyelination, the shorter the life span. However, we have previously described jimpy-msd mice that survive twice as long as usual; although they acquire significantly increased amounts of myelin, they still succumb long before their unaffected littermates. This result contradicts any postulated causal relationship between extent of CNS hypomyelination and premature death of the animal. Here we have addressed this question in another way, by using an animal model that does not involve a proteolipid protein (Plp) gene mutation. We demonstrate that quaking*shiverer double-mutant mice can survive for at least 100 days without any CNS myelin whatsoever. Therefore, at least for a mouse, absence of CNS myelin is not lethal per se.

Animals↗
PubMed1984

Myelin basic protein gene expression in quaking, jimpy, and myelin synthesis-deficient mice.

Jimpy (jp), myelin synthesis-deficient (jpmsd), and quaking (qk) are mutations which affect myelination to different degrees in the mouse central nervous system (CNS). Total messenger RNA (mRNA) and myelin basic protein (MBP)-specific mRNA from brains of these three mutants have been analyzed by in vitro translation and immunoprecipitation with antibody to MBP. The results indicate that the three mutations do not affect the level of total MBP-specific mRNA in the CNS but do affect the relative proportions of the various MBP-related translation products encoded in vitro. In each case the proportions of 14K and 12K Mr MBP-related translation products are reduced and the proportions of 21.5K, 18.5K, and 17K Mr MBP-related translation products are increased relative to wild type. This effect is most pronounced in jp, less so in jpmsd, and least pronounced in qk animals. The MBP-related polypeptides that accumulate in vivo have also been analyzed in the three mutants by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by immunoblotting with antibody to MBP. The levels of all the major MBP-related polypeptides that accumulate in vivo are reduced in all three mutations. The reduction is most pronounced in jp, less in jpmsd, and least pronounced in qk animals. These results indicate that the jp, jpmsd, and qk mutations exhibit qualitatively similar phenotypic effects on MBP gene expression but the magnitude of the effect is proportional to the extent of hypomyelination in each mutant.

Animals↗
PubMed2004

Deletion of the Parkin coregulated gene causes male sterility in the quaking(viable) mouse mutant.

Quaking(viable) (qk(v)) is a recessive neurological mouse mutation with severe dysmyelination of the CNS and spermiogenesis failure. The molecular lesion in the qk(v) mutant is a deletion of approximately 1 Mb on mouse chromosome 17 that alters the expression of the qk gene in oligodendrocytes. Complementation analysis between the qk(v) mutation and qk mutant alleles generated through chemical mutagenesis showed that the male sterility is a distinctive feature of the qk(v) allele. This observation suggested that the sperm differentiation defect in qk(v) is due to the deletion of a gene(s) distinct from qk. Here, we demonstrate that the deletion of Pacrg is the cause of male sterility in the qk(v) mutant. Pacrg is the mouse homologue of the human PARKIN-coregulated gene (PACRG), which encodes for a protein whose biochemical function remains unclear. We show that Pacrg is highly expressed in the testes in both mice and humans. In addition, the expression pattern of Pacrg during spermiogenesis suggests that it plays a role in sperm differentiation. In support of this hypothesis, we show that transgenic expression of Pacrg in testes restores spermiogenesis and fertility in qk(v) males. This finding provides the first in vivo evidence, to our knowledge, for the function of Pacrg in a model organism. Immunolocalization experiments on isolated spermatozoa show that the Pacrg protein is present in mature sperm. Remarkably, the mammalian Pacrg protein shares significant sequence similarities with gene products from flagellated protozoans, suggesting that Pacrg may be necessary for proper flagellar formation in many organisms.

Amino Acid Sequence↗
PubMed1978

The preparation and analysis of myelin from small quantities of central nervous tissue: regional studies of the quaking mouse.

Myelin of considerable purity may be isolated from small (minimum 1 mg wet weight) samples of central nervous tissue, using a 4-step centrifugation procedure. The separation of myelin proteins by micro-linear gradient polyacrylamide gel electrophoresis yields similar results to those obtained by macro-scale (homogeneous) gel systems. These techniques have been employed for a preliminary study of the regional composition of myelin fractions from the Quaking mouse.

Animals↗
PubMed1991

31P-NMR study of brain phospholipid structures in vivo.

31P-NMR has been used extensively for the study of cytosolic small molecule phosphates in vivo and phospholipid structures in vitro. We present in this paper a series of studies of the brain by 31P-NMR, both in vivo and in extracts, showing the information that can be derived about phospholipids. 31P-NMR spectra of mouse brain at 73 mHz are characterised by almost a complete absence of the large phosphodiester peak in comparison to equivalent spectra at 32 mHz. Proton decoupled spectra in vivo, and spectra of extracts, show that the phosphodiester peak observed in 32 mHz spectra in vivo is mainly due to phospholipid bilayers. Homogenates of quaking and control mouse brains, and of bovine grey matter, show another narrower phosphodiester peak possibly from small phospholipid vesicles. This peak is increased in intensity in the affected mice. These experiments demonstrate the presence of three major components contributing to the phosphodiester resonance: bilayer phospholipids, more mobile phospholipids, and the freely soluble cytosolic molecules glycerophosphocholine and glycerophosphoethanolamine. These NMR methods for non-invasive investigation of phospholipid structures in the brain might be extended to studies of patients with membrane involved diseases such as multiple sclerosis.

Animals↗