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PubMed2004

Increased NG2(+) glial cell proliferation and oligodendrocyte generation in the hypomyelinating mutant shiverer.

Glial cells that express the NG2 proteoglycan (NG2(+) cells) are considered to be oligodendrocyte progenitors (OPCs) in the central nervous system (CNS), based on their ability to give rise to mature oligodendrocytes in vitro. To understand how dysmyelinated conditions influence OPC proliferation and differentiation, we studied proliferation and differentiation of NG2(+) OPCs in vivo in the shiverer mutant (shi), which do not form compact myelin due to a deletion in the myelin basic protein gene. Acute bromodeoxyuridine (BrdU) labeling studies revealed a 4- to 6-fold increase in NG2(+) cell proliferation in shi spinal cord between postnatal day18 (P18) and P60, and most BrdU(+) cells were NG2(+) after P18. The increased proliferation was accompanied by a 2-fold increase in the number of OPCs and oligodendrocytes. Survival studies following a single injection of BrdU at P18 revealed a decline in the number of BrdU(+)/NG2(+) cells with a concomitant increase in the number of BrdU(+) oligodendrocytes over time, suggesting that the proliferated NG2(+) cells had differentiated into oligodendrocytes. BrdU(+) oligodendrocytes were generated over a longer period of time in shi spinal cord and persisted longer in shi than in wild type spinal cord. These findings suggest that new oligodendrocytes continue to be generated in the dysmyelinated shi spinal cord by enhanced proliferation and differentiation of NG2(+) oligodendrocyte progenitor cells.

Animals↗
PubMed1990

Immunohistochemical studies on cross-transplantations between jimpy, shiverer, and normal newborn mice.

Cross-transplantations of neural tissue have been performed between jimpy (jp), shiverer (shi), and normal mice. Taking advantage of the absence of immunodetectable myelin basic protein (MBP) in the shi brain, jp myelin has been identified in the shi recipient by using an anti-MBP antiserum. By contrast, shi as well as normal myelin have been identified in the jp brain by using an anti-C-terminal hexapeptide of the proteolipid protein (PLP) (this PLP hexapeptide being absent in the jp PLP). When transplanted under homochronic conditions (newborn into newborn), jp oligodendrocytes (ODC) express their usual phenotype in a normal or a shi environment, suggesting that at birth the jp ODCs phenotype is strictly established and cannot be modified by environmental conditions. The reverse transplantations (newborn shi or normal into newborn jp brain) demonstrate that the jp environment does not modify the phenotype of normal or shi ODCs. Finally, these experiments demonstrated a normal timing of differentiation of jp axons and of jp ODCs.

Animals↗
PubMed1978

Non shivering thermogenesis and implication of the thyroid in cold labile and cold resistant populations of the golden spiny mouse (Acomys russatus).

The golden spiny mouse is dependent on non shivering thermogenesis (N.S.T.) for thermoregulation at cool ambient temperatures. Mice from the shores of the Dead Sea (Ein-Gedi, EG-mice) lose body heat when exposed to 6 degrees C. Their rate of cooling is linearly correlated to the magnitude of N.S.T. This is true for mice acclimated to 28 degrees C, born in the laboratory or freshly captured. Mice from the high mountains of South Sinai (S-mice) resist cooling under the same conditions and their N.S.T. is about twice that of EG-mice. EG-mice did not acclimate to cold. However thyroxine injections made them cold resistant and their N.S.T. rose to values close to that of S-mice. Light and electronmicroscopy of the thyroids in mice acclimated to 28 degrees C and exposed to 6 degrees C, or injected with TRH suggested intense activity in S-mice and little activity in EG-mice.

Acclimatization↗
PubMed1978

Control of non-shivering thermogenesis in a hibernator.

Present experiments indicate that in hedgehogs two different control mechanisms of non-shivering thermogenesis (NST) exist. During arousal from hibernation catecholamines control heat production in the interscapular brown adipose tissue. In a non-hibernating state, cold-induced NST is controlled by a desoxycorticosterone-like acting compound. The effector system of this second mode of NST is obviously not the interscapular brown fat but a layer of brown adipose tissue which covers the whole back of the hedgehog.

Animals↗
PubMed1989

Glial hyaluronate-binding protein in dysmyelinating mice mutants: jimpy, quaking and shiverer.

Cryostat sections of cerebral hemispheres, cerebellum and spinal cord from dysmyelinating mice mutants (quaking, jimpy and shiverer) and littermate controls were stained by indirect immunofluorescence with polyclonal antibodies to the glial hyaluronate-binding protein (GHAP), a brain-specific extracellular matrix glycoprotein produced by astrocytes. In normal mice, the distribution of GHAP was similar to that previously reported in human, calf, pig and dog. The antigen was mainly localized in white matter, the granular layer of the cerebellum being the main exception. No differences were observed between mutants and littermate controls, except that with both GHAP and glial fibrillary acidic protein antibodies the glial framework was denser in the mutants, probably due to the reduction in myelin. The findings suggest that GHAP expression by astrocytes is not induced by myelination and that white matter astrocytes constitute a distinct glial population.

Animals↗
PubMed1983

Developmental changes of oligodendroglia in the posterior funiculus of "Shiverer" mutant mouse spinal cord, with special reference to myelin formation.

Oligodendroglia in the "Shiverer" spinal cord at 2, 4, 8 and 18 weeks of age were investigated by electron microscopy, with special reference to the process of myelin formation. The predominant changes observed were vacuolization of the cytoplasm during 2 and especially 4 weeks of age, indicating initial steps in the formation of myelin sheaths, although their total volumes was very small and their lamellae were incomplete. Polymorphic vacuoles and vesicles with various electrondense contents appeared to originate from the Golgi complex and the rough-surfaced endoplasmic reticulum (r-ER), since such vacuoles happened to be continuous with the Golgi complex, and the Golgi complex disappeared concomitantly with the appearance of great numbers of vacuoles. The r-ER was also fragmented together with the occurrence of vesicles. After 8 weeks of age, the number of myelinated nerve fibers reached the plateau of the increasing curve, while the number of myelin lamellae successively increased until the sheaths were completed. At these stages the oligodendroglia containing vacuoles gradually disappeared, although numerous oligodendroglia possessing a nucleus with peripheral, densely clumped chromatin were present. These dark oligodendroglia contained a Golgi complex, r-ER with small, single cisternae and microtubules of irregular thickness, different from those found in the control oligodendroglia. At 18 weeks of age polymorphic vacuoles had disappeared in most oligodendroglia.

Animals↗
PubMed1983

Decreased capacity for non-shivering thermogenesis during lactation in mice.

The capacity for non-shivering thermogenesis (NST) has been measured during and after lactation in mice. NST was found to be reduced in early and mid-lactation and at the time of weaning, the reduction being greatest at mid-lactation. By one week after weaning, however, the capacity for NST had returned to the level in virgin animals.

Animals↗
PubMed1995

The number of Schmidt-Lanterman incisures is more than doubled in shiverer PNS myelin sheaths.

In the PNS, myelin basic protein (MBP) appears not to be essential for myelination, for in shiverer (shi) and mld mutant mice peripheral nerves, where MBP is not or only poorly expressed, myelination occurs normally. Only a few morphological abnormalities, i.e. reduction in axon calibre and myelin sheath thickness, and aberrant Schwann cell-axon contacts, have been reported. Here, we document a consistent difference between shi and wild type (wt) myelinated sciatic nerve fibres. The number of Schmidt-Lanterman incisures seen in longitudinally and transversely-sectioned sciatic nerves, or in teased fibres stained for the presence of F-actin, is dramatically increased in homozygous shi mice. With both methods, a twofold increase in Schmidt-Lanterman incisure number is seen in 15-day-old mice, the earliest time examined. The increase is slightly greater in nerve fibres from 30- and 90-day-old mice. The overproduction of Schmidt-Lanterman incisures in shi occurs in spite of the fact that the mean diameter of myelinated fibres in shi sciatic nerves is smaller than in wt sciatic nerves. These results lead us to suggest that the increase in Schmidt-Lanterman incisure density in shi compensates for a defect in Schwann cell-axon communication.

Actins↗
PubMed1993

Regional and developmental variations of GFAP and actin mRNA levels in the CNS of jimpy and shiverer mutant mice.

Gliosis is a common reaction to brain damage. Glial fibrillary acidic protein (GFAP) is a classical astrocytic marker. We have undertaken to measure the level of GFAP-mRNA as an index of gliosis in the brain of jimpy (jp) and shiverer (shi) murine mutants, in which hypomyelination is either severe or moderate, respectively. This study was conducted in five different CNS regions and at different ages. In young jp mutant, the amount of GFAP-mRNA was either normal or lower than in control animals; but after 3 wk of age, the level of GFAP-transcript increased dramatically in all regions examined. A parallel increase in actin-mRNA was also observed, mostly in the diencephalon and to a lesser extent in cortex and spinal cord, but not in the cerebellum and brainstem. In the shi mutant, variations in the amount of GFAP-mRNA were less important than in the jp with two exceptions: In brainstem of 3-wk-old animals, a 2.5-fold increase was observed, and in all the regions but the spinal cord of 12-d-old shi, the levels of GFAP-transcript were 2-5 times lower than in controls. In this mutant, the levels of actin message were usually close to normal, or slightly lower than in controls.

Actins↗
PubMed1986

Biochemical and physicochemical determinations in a premyelin fraction obtained by zonal centrifugation in normal mouse and in dysmyelinating mutants (quaking, shiverer, and myelin-deficient).

Myelin and premyelin material denser than myelin were obtained from quaking (Qk), shiverer (Shi), and myelin-deficient (mld) mutant and control mice, using zonal centrifugation on zonal rotor. On these fractions, we performed biochemical analysis (lipids and fatty acid), and, in parallel, we determined the physical structure of membranes by the spin-label method. The hyperfine splitting constant (2 Tll) was used to determine the order of membranes and their rigidity, and frequency of rotation (Vc) was used to measure fluidity. In control mice, the premyelin material contained a lesser amount of sphingolipids than pure myelin, but the relative proportions between hydroxy- and nonhydroxy-cerebroside and sulfatides were similar in the premyelin material and in pure myelin. The premyelin material contained half the alkanes found in the pure myelin and much less very-long-chain fatty acids. The (2 Tll) was lower in the premyelin material, but the (Vc) was similar in myelin and premyelin material. In mutants, the amount of material recovered in the premyelin fraction was reduced in qk, and increased in both shi and mld. The relative amount of sphingolipids were normal in mld, but not in shi mutants, especially in cerebrosides formed with alpha-hydroxylated fatty acids and sulfatides formed with unsubstituted fatty acids. The absolute amounts of sphingolipids were nearly normal in both shi and mld. In the premyelin fraction from qk mutants, both relative and absolute amounts of sphingolipids were drastically altered. In percentage, cerebrosides and sulfatides formed with nonhydroxyfatty acids were dramatically reduced, and, conversely, cerebrosides and sulfatides formed with hydroxyfatty acids were increased. In terms of absolute amount, only cerebrosides and sulfatides formed with nonhydroxyfatty acids were dramatically reduced. In the premyelin fraction, polyunsaturated fatty acids were increased in shi and mld, but decreased in qk. In this mutant, lignoceric (24:0) and nervonic (24:1) acids were drastically reduced. The amount of alkanes in the premylin material from qk and mld was reduced by 50%. The shi fraction was nearly free of alkanes. The maximal apparent coupling constant (hyperfine splitting constant, 2 Tll) was not affected in the mld and qk mutant, but was reduced in the shi mutant premyelin fraction. The Vc was dramatically increased in the qk, slightly decreased in the shi, and close to control in the mld. This work provides additional data on premyelin material prepared in various neurological mutants using continuous gradients in zonal rotor.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkanes↗
PubMed1981

Fine structure of the central myelin sheath in the myelin deficient mutant Shiverer mouse, with special reference to the pattern of myelin formation by oligodendroglia.

The central myelin sheaths of the recessive autosomal mutant mouse, Shiverer, were investigated by electron microscopy with special reference to the pattern of myelin formation. The results obtained may be summarized as follows: (1) the major dense line of myelin lamellae generally failed to be formed, but the axons were enclosed by tri-lamellar structures of about 14 nm in width, which were composed of one central membrane formed by fusion of outer leaflets of adjacent cytoplasmic sheets of oligodendroglia, corresponding to the intraperiod line, and two outer membranes which were identical with inner leaflets of adjacent cytoplasmic sheets and became highly electron-dense. However, major dense lines were sporadically observed; (2) the myelin sheath was not generally formed by spiralling of one cytoplasmic process of the oligodendroglia, but by enclosing an axon with several stratified layers of cytoplasmic sheets, some of which were certainly formed by the splitting of one process; and (3) aberrant myelination frequently occurred around the soma of oligodendroglia, not related to any axons.

Animals↗
PubMed1986

Transplantation of bulk-separated oligodendrocytes into the brains of shiverer mutant mice: immunohistochemical and electron microscopic studies on the myelination.

Normal oligodendrocytes were separated from 7-day-old mouse (BALB/c) brains by the Percoll gradient method. Immunohistochemical staining with an anti-galactocerebroside serum revealed that about 85% of the separated cells were oligodendrocytes. The oligodendrocytes were transplanted into the corpus striatum of 4-week-old shiverer mutant mice which are characterized by the lack of myelin basic protein (MBP). Myelination by the implanted oligodendrocytes was investigated immunohistochemically and electron microscopically 6 weeks after the operation. Certain areas in the corpus striatum were intensely stained with antiserum to MBP. Electron microscopic examination showed that some axons were surrounded by normal type myelin sheaths with major dense lines. These results clearly indicate that matured oligodendrocytes are able to survive and myelinate the host axons even in the adult brain.

Animals↗
PubMed1991

Normal rate of Schwann cell proliferation in the MBP-deficient shiverer mouse during Wallerian degeneration.

Myelin basic protein (MBP) processed by macrophages was reported to promote Schwann cell division during Wallerian degeneration. In the present study we have shown that there was no difference in the rate of Schwann cell proliferation between shiverer mice, which totally lack MBP, and control mice after nerve-transection. Furthermore, addition of autologous peritoneal macrophages in cultures led to enhanced thymidine uptake by Schwann cells, irrespective of the presence or absence of MBP. These results suggest that myelin components other than MBP play a role in Schwann cell proliferation induced by macrophages.

Animals↗
PubMed1985

The distribution of 2':3'-cyclic nucleotide 3'-phosphodiesterase (CNP) in the CNS of normal (+/+) and shiverer (Shi/Shi) mice.

Immunohistochemical techniques were utilized to localize the putative myelin enzyme 2':3'-cyclic nucleotide 3'-phosphodiesterase (CNP) in the central nervous system (CNS) of normal (+/+) and Shiverer (Shi/Shi) mice (Mus musculus). CNP appeared to be only associated with myelinated nerve fibers in the CNS (corpus callosum, subcortical white matter, caudate nucleus, cerebellum and medulla oblongata) of +/+ mice. However, little or no immunostaining was observed in the same regions of the CNS of Shi/Shi mice, although these mice have normal levels of a CNS CNP activity. Unexpectedly, oligodendrocytes (cell periphery) were not stained for CNP in either +/+ or Shi/Shi mice, although erythrocytes were immunostained.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1988

Myelination by oligodendrocytes isolated from 4-6-week-old rat central nervous system and transplanted into newborn shiverer brain.

Oligodendrocytes isolated from 4-6-week-old rat brains were transplanted into newborn shiverer brains. Cells were identified as mature oligodendrocytes both by immunocytological and ultrastructural criteria. Normal myelin was detected using immunolocalisation (with an anti-MBP antiserum) and electron microscopy (presence of the major dense line). Patches of normal myelin (made by transplanted oligodendrocytes), widely spread throughout the host brains, were detected between 20 and 130 days after grafting. No sign of acute rejection was observed, but the graft became progressively delimited by astrocytic processes forming a continuous basal lamina.

Animals↗
PubMed1984

Effects of fasting and aminophylline on norepinephrine-stimulated non-shivering thermogenesis.

In an attempt to further elucidate the mechanisms of fasting-depressed maximum thermogenesis and cold tolerance, norepinephrine (NE)-stimulated non-shivering thermogenesis (NST) in cold-acclimated rats was used as a functional index of possible alterations in adrenergic efficacy after fasting. Fasting decreased the magnitude of maximum NE-Stimulated NST by 18.2% [6.87 +/- 0.47 Kcal (Kg X 75 X min)-1 well-fed vs. 5.81 +/- 0.39 Kcal (Kg X 75 X min)-1 fasted], but the apparent adrenergic binding affinity was not affected [Ke = 0.43 micrograms NE min-1 well-fed vs. 0.55 micrograms NE min-1 fasted]. Pretreatment with aminophylline [15 mg Kg-1, i.p.], a phosphodiesterase inhibitor, restored the fasting-depressed NE-stimulated NST to the fed level. The results suggest that the depression of maximum thermogenesis after fasting is not due to changes in adrenergic binding characteristics but to alteration in cAMP production/degradation, resulting in decreased substrate mobilization for thermogenesis.

Aminophylline↗
PubMed1986

Genotype-specific myelin formation around normal axons in cytosine arabinoside-treated organotypic cultures injected with normal or shiverer optic nerve.

Organotypic cultures of newborn mouse cerebellum, treated with 'antimitotic' drugs to prevent myelination, contain abundant large neurons and axons but no mature oligodendroglia and no myelin. When oligodendroglia, contained in optic nerve fragments from 7-12-day-old normal or shiverer mutant mouse, are added to the cultures, myelin is formed in the vicinity of the optic nerve explant. The phenotype of the added myelin corresponds to the genotype of the optic nerve added, indicating that the added oligodendroglia are making the myelin themselves rather than contributing a diffusible factor which stimulates native cerebellar oligodendroglia or their precursors. This system will be valuable for direct, detailed comparisons of myelin formation by normal and mutant oligodendrocytes.

Animals↗
PubMed1989

Non-shivering thermogenesis and obesity in adult diabetic Wistar fatty rats.

1. Characteristics of resting and of norepinephrine (NE)-stimulated thermogenesis, and the glycemic response to NE were determined in adult male Wistar Fatty rats. Rats were maintained on Purina chow No. 5001 until 22 weeks of age, and fed semisynthetic diets containing 54% carbohydrate, 20% protein, 16% mixed fats, plus essential vitamins, minerals, and non-nutritive fiber from 22 until 30 weeks of age. 2. Obese rats were 50% heavier than lean throughout the study. Phenotype effects (obese greater than lean) were present for retroperitoneal (RP) and dorsal (DOR) white fat depot weight, adipocyte number per depot, and adipocyte lipid content. Epididymal mass and cellularity were similar in both phenotypes. 3. Interscapular brown adipose tissue (IBAT) mass, adipocyte size, and adipocyte number were greater in obese than in lean. Resting metabolic rates (RMR) of obese rats were lower than in lean, and increased 79% in lean but only 33% in obese animals following NE (200 micrograms/kg BW, s.c.) stimulation. 4. The glycemic response to NE occurred normally in both phenotypes, and resulted in a 3-fold increment in plasma glucose in lean rats and a 5-6-fold increase in plasma glucose in obese rats. 5. The results of this study are consistent with hyperplasia and hypertrophy of IBAT, RP and DOR depots, and indicate that the capacity for non-shivering thermogenesis is impaired in the obese phenotype of this strain in spite of peripheral sensitivity to NE and greater mass and cellularity of brown adipose tissue.

Adipose Tissue↗