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PubMed1983

Altered brain copper and zinc content in quaking mice.

Brain copper and zinc levels were determined in 21-day-old and "adult" C3HeB/FeJ quaking mice and in normal littermate controls. Expressed per gram dry weight of brain, copper was increased 84% over normal mice at 21 days after birth, but was not significantly different from normal in the adults. Zinc was increased 23 to 24% at both ages. At both ages, brains from quaking mice had a significantly reduced content of solids, indicating increased water content in the mutant brain. Our study is the first to report copper and zinc content as a measure of both wet and dry brain weights. Our results indicate abnormal copper content in the quaking mutant. The relationship between copper content and other aspects of the quaking phenotype, including its seizure behavior and myelin deficit, remain to be established.

Aging↗
PubMed1983

[Hereditary demyelination in mutant quaking mice (electron microscopy study)].

Light and electron microscopic examinations of the nervous system in autosomal recessive mutant Quaking mice varying in ages from 12 days to 4 months revealed significant dysmyelination in which one of the most important morphological manifestations consisted of formation of "watery" astrocytes. The primary edema of astrocytes extended to other cerebral structures and produced their vacuolation, as a result of which significant disorders in the normal process of myelogenesis were observed, such as a decrease in the total volume of the white matter because of underdevelopment of myelin, disorders of the function of myelin-forming cells, oligodendrocytes. Pathological changes were also observed in some neurons and synapses. In contrast to the current opinion, the authors believe dysmyelination to be due not to primary involvement of oligodendrocytes but to edema of astrocytes. This does not rule out the genetic nature of this disease.

Animals↗
PubMed1989

Developmental expression of 2',3'-cyclic-nucleotide 3'-phosphodiesterase mRNA in brains of normal and quaking mice.

A cDNA fragment of mouse 2',3'-cyclic-nucleotide 3'-phosphodiesterase was isolated and used as the probe for Northern blot analysis. The mRNA bands in normal mice became detectable at 10 days after birth, reached the maximum at the period of active myelination and then decreased gradually. At all stages of development studied, the mRNA bands in quaking mice were markedly reduced as compared with those in normal mice.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1980

Developmental changes in carbonic anhydrase and adenylate cyclase in quaking mice.

The present investigation focuses on the developmental changes in the activity and levels of carbonic anhydrase, adenylate cyclase and 3',5'-cyclic adenosine monophosphate (cAMP) in the Quaking mouse mutant in different regions of the brain. Carbonic anhydrase activity was found to be lower than normal in the forebrain of the C57/B Quaking mouse. The deficit in forebrain carbonic anhydrase was restricted to subcortical structures and was reflected equally in the membrane and soluble factions, indicating that neither pool was affected selectively. However, no difference in carbonic anhydrase activity was observed in purified myelin from Quaking and control mice. Investigation of the changes in carbonic anhydrase activity as a function of age showed a cessation in enzyme accumulation in Quaking mice at around 20 days postnatally, suggesting an abnormality in cellular development. A tritiated acetazolamide binding assay was used to quantitate the amount of enzyme present. The amount of carbonic anhydrase parallelled enzyme activity, suggesting that the defect in the Quaking animals was at the level of the control of enzyme synthesis. Similar studies on cyclic AMP metabolism showed a higher than normal adenylate cyclase activity in the upper brain stem region of Quaking mice of ages between 19 and 40 days. Adenylate cyclase activity was stimulated by norepinephrine in both control and Quaking animals. The increased adenylate cyclase activity in the Quaking mice was in contrast to a lower cyclic AMP level and could not be accounted for by an alteration in phosphodiesterase activity.

Adenylyl Cyclases↗
PubMed1976

[Comparative biosynthesis of fatty acids, particularly lignoceric acid, in the kidney and brain of normal and "quaking" mice].

Palmityl-CoA elongation is normal in kidney and brain from Quaking mice. However elongation of stearyl-CoA and behenyl-CoA is disturbed in the mutant brain, but not in kidney. Moreove in both organs, the reaction products are the same in normal and Quaking animals. Thus the microsomal biosynthesis of very long chain fatty acid biosynthesis is normal in Quaking kidney and not in brain : the genetic control of elongating enzymes must be different according to the organ.

Animals↗
PubMed1975

Hyperplasia of oligodendrocytes in quaking mice.

The number of neuroglial cells in selected fiber tracts of 90-day-old quaking and normal mice was determined by a combination of light and electron microscopy. Oligodendrocytes of quaking mice are normal in number in the anterior commissure and corticospinal tract (in the cervical spinal cord) but are increased two- to fourfold in the optic nerve and the fasciculi cuneatus and gracilis (in the cervical spinal cord). The nuclei and perikarya are normal in size or smaller than normal. Those tracts with the greatest hyperplasia of oligodendrocytes also have the greatest content of myelin, suggesting that cell number influences content of myelin. However, the volume of myelin per oligodendrocyte also varies, between 2 and 11% of normal, in the different tracts of the mutant. The hyperplasia of oligodendrocytes in quaking mice may arise as compensation for their decreased production of myelin and reflect a normal plasticity in the processes of myelination. If so, the mutant may be a useful system for study of the regulation of myelogenesis.

Animals↗
PubMed2002

Nuclear retention of MBP mRNAs in the quaking viable mice.

Quaking viable (qk(v)) mice fail to properly compact myelin in their central nervous systems. Although the defect in the qk(v) mice involves a mutation affecting the expression of the alternatively spliced qk gene products, their roles in myelination are unknown. We show that the QKI RNA binding proteins regulate the nuclear export of MBP mRNAs. Disruption of the QKI nucleocytoplasmic equilibrium in oligodendrocytes results in nuclear and perikaryal retention of the MBP mRNAs and lack of export to cytoplasmic processes, as it occurs in qk(v) mice. MBP mRNA export defect leads to a reduction in the MBP levels and their improper cellular targeting to the periphery. Our findings suggest that QKI participates in myelination by regulating the mRNA export of key protein components.

3' Untranslated Regions↗
PubMed1984

Immunocytochemical studies of quaking mice support a role for the myelin-associated glycoprotein in forming and maintaining the periaxonal space and periaxonal cytoplasmic collar of myelinating Schwann cells.

The myelin-associated glycoprotein (MAG) is an integral membrane glycoprotein that is located in the periaxonal membrane of myelin-forming Schwann cells. On the basis of this localization, it has been hypothesized that MAG plays a structural role in (a) forming and maintaining contact between myelinating Schwann cells and the axon (the 12-14-nm periaxonal space) and (b) maintaining the Schwann cell periaxonal cytoplasmic collar of myelinated fibers. To test this hypothesis, we have determined the immunocytochemical localization of MAG in the L4 ventral roots from 11-mo-old quaking mice. These roots display various stages in the association of remyelinating Schwann cells with axons, and abnormalities including loss of the Schwann cell periaxonal cytoplasmic collar and dilation of the periaxonal space of myelinated fibers. Therefore, this mutant provides distinct opportunities to observe the relationships between MAG and (a) the formation of the periaxonal space during remyelination and (b) the maintenance of the periaxonal space and Schwann cell periaxonal cytoplasmic collar in myelinated fibers. During association of remyelinating Schwann cells and axons, MAG was detected in Schwann cell adaxonal membranes that apposed the axolemma by 12-14 nm. Schwann cell plasma membranes separated from the axolemma by distances greater than 12-14 nm did not react with MAG antiserum. MAG was present in adaxonal Schwann cell membranes that apposed the axolemma by 12-14 nm but only partially surrounded the axon and, therefore, may be actively involved in the ensheathment of axons by remyelinating Schwann cells. To test the dual role of MAG in maintaining the periaxonal space and Schwann cell periaxonal cytoplasmic collar of myelinated fibers, we determined the immunocytochemical localization of MAG in myelinated quaking fibers that displayed pathological alterations of these structures. Where Schwann cell periaxonal membranes were not stained by MAG antiserum, the cytoplasmic side of the periaxonal membrane was "fused" with the cytoplasmic side of the inner compact myelin lamella and formed a major dense line. This loss of MAG and the Schwann cell periaxonal cytoplasmic collar usually resulted in enlargement of the 12-14-nm periaxonal space and ruffling of the apposing axolemma. In myelinated fibers, there was a strict correlation between the presence of MAG in the Schwann cell periaxonal membrane and (a) maintenance of the 12-14-nm periaxonal space, and (b) presence of the Schwann cell periaxonal cytoplasmic collar.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1978

[Study of gangliosides in normal (C57B1/6J) and quaking mice. Presence and characterization of a labile ganglioside in alkaline solution].

In the adult Quaking mutant, there is an increase in some polysialogangliosides (GT1 and Gq) and a 50% decrease in BM1 content. Thus, the latter ganglioside, which is a constituent of mature myelin, could be linked to one of the late steps of the myelination process. A novel ganglioside ALG1, which appears during the postnatal development of brain, has been isolated and purified; it contains an alkali labile linkage and after alkaline treatment yields GT1b. Comparison between normal Mice and Quaking mutants does not show any significant quantitative differences, under our conditions. At the stage at which it appears, it could be linked to steps of brain maturation other than myelimation.

Animals↗
PubMed1982

Development of membrane-bound carbonic anhydrase and glial fibrillary acidic protein in normal and quaking mice.

The developmental patterns of membrane-bound carbonic anhydrase (MBCA) and glial fibrillary acid protein (GFA) were analyzed in high speed pellets from subcortical regions of quaking and control mice at ages ranging from 10 to 42 days. In control, MBCA was found to increase from approximately 1.5 unit/mg protein at 10 days to about 11 units/mg protein at 42 days. The percent increase was greatest between days 11 and 18 where the activity increased 2.5-fold while the largest absolute weekly increment was in the fourth postnatal week. By contrast, the activity in quaking mice was 1.0 units/mg protein at day 10 and increased to only 5 units/mg protein by 42 days. The activity, although reduced at 10 days, appeared to increase in parallel with the controls between day 11 and 18; however, the large increment in activity observed in the controls during the fourth week was greatly reduced in the mutant. The above findings were also observed when immune reactive material was determined by immuno-blotting using antisera raised against MBCA isolated from brain. GFA was also estimated using an immuno-blotting procedure. In contrast to previous studies on soluble GFA, we found GFA to increase about 5-fold in the third postnatal week and level off thereafter. The Q/C ratio was 1.5 at 10 days, but, although GFA increased over 5-fold between 11 and 42 days, the absolute difference between quaking and control increased very little. These data on GFA and MBCA suggest that a defect in the expression of oligodendroglial plasma membrane proteins may be expressed early in development which may correlate with a small but significant gliosis and/or an increase in GFA synthesis.

Aging↗
PubMed1979

Myelin basic proteins in myelin subfractions from normal and quaking mice.

The relative proportions of four myelin basic proteins (preL, L, preS,S) were determined in myelin subfractions prepared from the forebrains of quaking and littermate control mice. The distribution pattern of each protein was similar in both mutant and control fractions. The S component was the only basic protein present in low amounts in myelin from the mutant.

Animals↗
PubMed1983

Protein composition of PNS myelin: developmental comparison of control and quaking mice.

Protein compositions were determined for sciatic nerve myelin isolated from young and adult control and quaking (Qk) mice. Age-related changes in the relative amounts of large (Pl) and small (Pr) basic proteins were found. In control animals, the ratio Pr/Pl increased with age, a change similar to that observed for the large (Bl) and small (Bs) CNS myelin basic proteins of adult mice. Pr/Pl also increased with age in the Qk mouse sciatic nerve, but only to the point that the value in the adult Qk mouse was similar to that observed for young control animals, a situation reminiscent of the effect of the Qk mutation on CNS basic proteins. Thus, our data suggest that the Qk mutation has a similar effect on peripheral nervous system (PNS) and CNS basic proteins. Our findings are consistent with recent electrophoretic and immunochemical data showing that PNS and CNS myelin basic proteins in rodents are analogous, and they suggest that the genetic program controlling basic protein expression is common to oligodendroglia and Schwann cells.

Aging↗
PubMed1976

The (Na+ + K+)-ATPase activity in brain of Quaking mice.

The (Na+ 4 K+)- and Mg2+-dependent ATPase distribution in several brain areas has been investigated in Quaking mutant mice characterized by myelin deficiency. A marked decrease of (Na+ + K+)-ATPase activity has been found in limbic structures, hypothalamus and cerebellum. The Mg2+-dependent activity did not change. A possible involvement of the impairment of the (Na+ + K+)-ATPase activity in the seizure susceptibility of this mice is discussed.

Adenosine Triphosphatases↗
PubMed1964

MUTANT MICE (QUAKING AND JIMPY) WITH DEFICIENT MYELINATION IN THE CENTRAL NERVOUS SYSTEM.

Two mutant mice with deficient myelination are described. Quaking is a new autosomal recessive mutant mouse with marked tremor of the hindquarters. The mice eat, swim, breed, and nurse well even though the entire central nervous system is very deficient in myelin by histological and chemical criteria. Myelin formation is impaired; no destruction is seen. Peripheral nerves are myelinated. Jimpy, a known sex-linked mutation, has similar but more severe symptoms and similar pathology, with the additional feature of sudanophilic (nonpolar) lipid distributed in some white-matter tracts. Both mutants offer new opportunities for study of the formation and functions of myelin.

Animals↗
PubMed1990

Two isoforms of myelin-associated glycoprotein accumulate in quaking mice: only the large polypeptide is phosphorylated.

We have shown that the developmentally regulated appearance of the two myelin-associated glycoprotein (MAG) polypeptides in normal mouse brain myelin does not reflect the developmental pattern of differential splicing of primary gene transcripts as determined earlier by RNase protection assays. Contrary to expectation, the large (L-MAG) and small (S-MAG) polypeptides are present in about equal amounts at a relatively early stage of myelination, day 24 or earlier. In quaking (qk) mutant mouse brain myelin, both MAG polypeptides are evident at all ages examined; the relatively greater abundance of S-MAG compared to L-MAG at early ages (days 18 and 22) confirms our earlier observation on in vitro translations of mRNA. At later ages (day 27 and beyond) both isoform are present in approximately equal amounts. The L-MAG but not the S-MAG polypeptide can be phosphorylated by kinases that are endogenous to isolated qk myelin, analogous to the phosphorylation we have observed in vivo in normal mice and in their isolated myelin.

Animals↗
PubMed1983

[Fractionation of a sciatic nerve homogenate from normal, trembler and quaking mice on a continuous sucrose gradient].

Two fractions, characterized by biochemical criteria [quantity and density of particulate material, localization of myelin specific protein--Po, P1 and Pr--and of 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) and of 5'-nucleotidase], were isolated from sciatic nerve homogenate of normal, Trembler and quaking, young and adult Mice, on a continuous sucrose gradient. The fraction, at 0.58-0.6 M, the richest in membrane particles contains the myelin. The fraction at 0.7-0.75 M should contain the plasma membrane of the Schwann cell which synthesizes myelin.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1973

Fatty acyl-coenzyme A elongation in brain of normal and quaking mice.

Microsomal enzyme systems from mouse brain that catalyze, respectively, the elongation of palmitoyl-coenzyme A (palmitoyl-CoA), stearoyl-CoA, or arachidyl-CoA appear and reach maximal activity at different times after birth of the animal. A specific C(20)-CoA elongating system exists in mouse brain in addition to the previously recognized C(16)-CoA and C(l8)-CoA elongating enzymes. The C(20)-CoA elongation system is severely reduced in the mutant quaking mouse.

Age Factors↗