Oligodendrocytes of the jimpy phenotype can be partially restored by environmental factors in vivo

Lachapelle, F.; Lapie, P.; Campagnoni, Anthony T.; Gumpel, M.

doi:10.1002/jnr.490290214

Cited by 24 publications

(21 citation statements)

References 30 publications

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“…Trophic factors could be supplied by other cells within microenvironments in the mutant CNS, or by replacement conditions in vitro. This theory fits our in vitro observations and would explain both the increased differentiation of jp OLs in heterotypic transplants 26 and the survival and partial differentiation of small numbers of jp OLs in situ. However, studies on transgenic PLP and DM20 knockouts 27,28 indicate that there must also be a dominant-negative consequence of the jp mutation.…”

Section: Jimpy Oligodendrocyte Survival and Differentiation Can Be Ensupporting

confidence: 88%

Programmed cell death without DNA fragmentation in the jimpy mouse: secreted factors can enhance survival

et al. 1999

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Jimpy is one of many related mutations affecting the myelin proteolipid protein gene that causes severe hypomyelination in the central nervous system (CNS). Underlying the hypomyelination is a failure of oligodendrocytes (OLs) to differentiate, and the premature death of large numbers of OLs during the developmental period. Previous light and electron microscopic evidence suggested that jimpy OLs die in a manner consistent with programmed cell death. We have used TUNEL staining as a biochemical marker for apoptosis in conjunction with immunostaining for OL and myelin markers. At 13 ± 14 days postnatal, a time when the number of dying OLs in jimpy CNS is increased more than five times normal, there are only modest increases (70% in spinal cord; 20% in cerebral cortex) in TUNEL labeled cells in mutant CNS tissues. The results in vitro are similar, and only a small per cent of TUNEL labeled cells have the antigenic phenotype of OLs. The discrepancy between numbers of dying and TUNEL labeled cells suggests either that most jimpy OLs do not undergo programmed cell death or that the biochemical pathways leading to their death do not involve DNA fragmentation which is detected by the TUNEL method. We also present evidence that jimpy OLs show increased survival and enhanced differentiation when they are grown in vitro in medium conditioned by cells lines which express products of the proteolipid protein gene. Cell lines expressing proteolipid protein and the alternatively spliced DM20 protein have differential effects on cell numbers and production of myelinlike membranes.

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Section: Jimpy Oligodendrocyte Survival and Differentiation Can Be Ensupporting

confidence: 88%

Programmed cell death without DNA fragmentation in the jimpy mouse: secreted factors can enhance survival

et al. 1999

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“…In order to analyse the modalities of these cells activation, their behaviour was studied by immunohistochemistry (IHC) of the myelin they synthesized in the host brain. In addition, these results were compared with results obtained in previous experiments using fragments of PVZ from newborn [18] and embryonic animals [19] as donors.…”

Section: Introductionmentioning

confidence: 90%

“…By contrast these experiments demon strated that the poor myelinating capacity of jp ODCs cannot be modulated by environmental conditions. Fi nally, these experiments suggested that the mitotic poten tial of jp precursor cells transplanted in a newborn envi ronment depends only on their stage of differentiation [18,19].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the very singular patchy pattern of myelin distribution observed in the mutant brain suggests a clonal distribution of mutant ODCs which are able or not to survive [16]. Several experiments demonstrated a high sensitivity of jp ODC phenotype to environmental factors: (1) soluble factors present in nor mal and absent (or unefficient) in jp astrocytes partially restore the mutant ODC phenotype in vitro [17]; (2) transplantation experiments using fragments of newborn or embryonic jp tissue [18,19] demonstrated that the survival of jp ODCs can be favoured when these cells are exposed to a non jp CNS environment during their em bryonic life [19]. By contrast these experiments demon strated that the poor myelinating capacity of jp ODCs cannot be modulated by environmental conditions.…”

Section: Introductionmentioning

confidence: 99%

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Oligodendrocytes from Jimpy and Normal Mature Tissue Can Be 'Activated' when Transplanted in a Newborn Environment

Lachapelle¹,

Lapie²,

Gumpel³

1992

Dev Neurosci

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Fragments of corpus callosum from P13 normal and jimpy (jp) mutant mice (containing only postmigrating precursors and differentiated oligodendrocytes (ODCs, some of them myelinating soon) have been transplanted into the thalamus of newborn shiverer (shi) mutant mice. The behaviour of transplanted ODCs has been assayed by immunohistochemistry of their myelin basic protein (MBP)-positive myelin synthesized in the host shi brain whose myelin is deprived of this component. ODCs and postmigrating precursors contained in P13 normal corpus callosum survived, migrated out of the graft and myelinated in the shi host parenchyme. The high ratio of positive cases observed was comparable to the one observed in previous experiments using fragments of newborn or embryonic normal tissue. When fragments of jp tissue were used as donors, postmigrating jp ODCs or precursors migrated on long distances out of the graft and synthesized large amounts of myelin as estimated by the size of the MBP-positive myelin patches present in the host shi brain. The extent of migration and the size of these myelin patches were more important than those observed in previous experiments using fragments of newborn or embryonic jp CNS as donors. By contrast, the low ratio of positive cases observed suggested that the survival of P13 jp ODCs or their postmigrating precursors cannot be restored by the newborn shi environment. In order to determine whether P13 jp ODCs were activated by a factor present in shi but absent in jp tissue, fragments of P13 jp corpus callosum were transplanted into newborn jp brains: large patches of MBP-positive myelin were observed around the graft and extending from the graft through the host brain. This last result compared with results obtained in previous experimental series using fragments of newborn or embryonic jp tissue suggests that the activation of postmigrating jp precursors or differentiated jp ODCs is not triggered by the soluble factor(s) which seems to modulate the survival of jp precursor cells during the embryonic life in vivo and during the perinatal period in vitro.

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“…This suggested that PL P gene expression may be related to the secretion of humoral factor(s) that influence maturation and survival of oligodendrocytes. Furthermore, a partial rescue of jimpy oligodendrocytes was observed when embryonic jimpy brain fragments were transplanted into brains expressing a wild-type PLP gene (Lachapelle et al, 1991). Finally, the number of oligodendrocytes present in mixed glial cell cultures containing conditioned media from cell lines expressing the PLP gene (G26 mouse oligodendroglioma, B104 rat neuroblastoma, and B16 mouse melanoma) (Ikenaka et al, 1992) was significantly higher than that of control cultures without conditioned media or those supplemented with conditioned medium from NIH3T3 fibroblasts, which do not produce DM20 (Nakao et al, 1995).…”

Section: Abstract: Oligodendrocyte Development; Myelin Proteolipid Pmentioning

confidence: 99%

Proteolipid Protein Gene Product Can Be Secreted and Exhibit Biological Activity during Early Development

et al. 1999

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A gene encoding myelin proteolipid protein (PLP) and its smaller isoform DM20 is expressed at least 1 week before myelination. Mutations within the gene cause abnormalities in the development of premyelinating oligodendrocytes, resulting in hypomyelinating disorders. These findings suggest a premyelinating function of the PLP gene products. We previously demonstrated that PLP gene expression is directly associated with secretion of a factor that increases the number of oligodendrocytes. Here we show that this activity is mediated by a secreted fragment containing the C-terminal portion of PLP. This factor increased the bromodeoxyuridine incorporation rate in both oligodendrocyte and astrocyte lineage cells; a synthetic peptide (PLP 215-232) exhibited a similar activity. Doseresponse curves of PLP and PLP peptide showed maximum activities at a concentration in the picomolar range, which decreased at higher concentrations. These observations demonstrate that a secreted PLP gene product exerts biological activity at a premyelinating stage before the major induction of the gene.

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Oligodendrocytes of the jimpy phenotype can be partially restored by environmental factors in vivo

Cited by 24 publications

References 30 publications

Programmed cell death without DNA fragmentation in the jimpy mouse: secreted factors can enhance survival

Programmed cell death without DNA fragmentation in the jimpy mouse: secreted factors can enhance survival

Oligodendrocytes from Jimpy and Normal Mature Tissue Can Be 'Activated' when Transplanted in a Newborn Environment

Proteolipid Protein Gene Product Can Be Secreted and Exhibit Biological Activity during Early Development

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