Maturation-dependent apoptotic cell death of oligodendrocytes in myelin-deficient rats

Grinspan, Judith B.; Coulalaglou, Markella; Beesley, Jacqueline; Carpio, David F.; Scherer, Steven S.

doi:10.1002/(sici)1097-4547(19981201)54:5<623::aid-jnr7>3.0.co;2-r

Cited by 32 publications

(25 citation statements)

References 66 publications

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“…Because the increase in proliferation of NG2ϩ cells is accompanied by an increase in the number of PDGF ␣Rϩ progenitor cells, the reduction in the number of differentiated oligodendrocytes must reflect cell death of late-stage progenitors or differentiated oligodendrocytes. This idea is consistent with morphological studies that have demonstrated that dying oligodendrocytes are more prevalent than dying progenitor cells in jp spinal cord (Skoff, 1982(Skoff, , 1995Grinspan et al, 1998).…”

Section: Discussionsupporting

confidence: 91%

Elevated Levels of the Chemokine GRO-1 Correlate with Elevated Oligodendrocyte Progenitor Proliferation in theJimpyMutant

Miller

Ransohoff

et al. 2000

J. Neurosci.

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The dysmyelinating mutant jimpy ( jp) arises from a point mutation in the mouse gene encoding proteolipid protein and is characterized by severe dysmyelination attributable to oligodendrocyte death. This mutant was used to investigate the regulation of oligodendrocyte progenitor proliferation in the postnatal spinal cord. At postnatal day 18, jp spinal cord contained a three-to eightfold greater number of proliferating oligodendrocyte progenitor cells than did wild-type (wt) spinal cord. Increased proliferation in jp spinal cord was accompanied by a twofold increase in the number of progenitor cells. Semiquantitative reverse transcriptase-PCR revealed no change in the level of mRNA encoding the platelet-derived growth factor A, transforming growth factor-␤, or insulin-like growth factor-I, all of which have been implicated as regulators of proliferation and differentiation of oligodendrocyte progenitor cells. There was, however, a 17-fold increase in the level of mRNA encoding the chemokine GRO-1 and a 5-to 6-fold increase in GRO-1 protein in the jp spinal cord. Double immunofluorescence labeling revealed elevated levels of GRO-1 in reactive astrocytes in jp spinal cord white matter. In vitro studies indicated that extracts from jp spinal cord stimulated oligodendrocyte progenitor proliferation. Furthermore, removal of GRO-1 from jp extracts by immunoprecipitation reduced the proliferation of progenitor cells to a level similar to that achieved by wt extracts. These findings suggest a novel mechanism by which proliferation of oligodendrocyte progenitor cells is regulated in the postnatal spinal cord in response to insult.

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Section: Discussionsupporting

confidence: 91%

Elevated Levels of the Chemokine GRO-1 Correlate with Elevated Oligodendrocyte Progenitor Proliferation in theJimpyMutant

Miller

Ransohoff

et al. 2000

J. Neurosci.

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“…Apoptosis in the developing brain was assessed by the terminal deoxynucleotidyl transferasemediated dUTP nick end-labeling (TUNEL) assay (Roche). TUNEL analyses were accomplished using 25 m cryosections and processed according to published protocols (Grinspan et al, 1998).…”

Section: Methodsmentioning

confidence: 99%

Genetic Analyses Demonstrate That Bone Morphogenetic Protein Signaling Is Required for Embryonic Cerebellar Development

Qin

Wine‐Lee²,

Ahn³

et al. 2006

J. Neurosci.

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The cerebellum has been a useful model for studying many aspects of neural development because of its relatively simple cytoarchitecture and developmental program. Yet, the genetic mechanisms underlying early differentiation and patterning of the cerebellum are still poorly characterized. Cell expression studies and culture experiments have suggested the importance of bone morphogenetic proteins (BMPs) in development of specific populations of cerebellar neurons. Here, we examined mice with targeted mutations in the BMP type I receptor genes Bmpr1a and Bmpr1b, to genetically test the hypothesis that BMPs play an inductive role in the embryogenesis of cerebellar granule cells. In Bmpr1a;Bmpr1b double knock-out mice, severe cerebellar patterning defects are observed resulting in smaller cerebella that are devoid of foliation. In mutants containing either single BMP receptor gene mutation alone, cerebellar histogenesis appears normal, thereby demonstrating functional redundancy of type I BMP receptors during cerebellar development. Loss of BMP signaling in double mutant animals leads to a dramatic reduction in the number of cerebellar granule cells and ectopic location of many of those that remain. Molecular markers of granule cell specification, including Math1 and Zic1, are drastically downregulated. In addition, Purkinje cells are disorganized and ectopically located, but they appear to be correctly specified. Consistent with the interpretation that granule cells alone are affected, phosphorylated Smad1/5/8 is immunolocalized predominantly to granule cell precursors and not appreciably detected in Purkinje cell precursors. This study demonstrates that BMP signaling plays a crucial role in the specification of granule cells during cerebellar development.

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“…Cell death was measured using the TUNEL analysis as previously described (Grinspan et al, 1998). To determine extent of cell death among oligodendrocyte and astrocyte populations specifically, sections were double-labeled with anti-cleaved caspase 3 (1:200, Cell Signaling) and anti-rabbit secondary antibody (1:100) and anti-PDGFRα or anti-GFAP, respectively.…”

Section: Immunohistochemistrymentioning

confidence: 99%

BMP signaling mutant mice exhibit glial cell maturation defects

See

Mamontov

Ahn

et al. 2007

Molecular and Cellular Neuroscience

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Bone morphogenetic proteins have been implicated in the development of oligodendrocytes and astrocytes, however, a role for endogenous BMP signaling in glial development has not been demonstrated in a genetic model. Using mice in which signaling via type I BMP receptors Bmpr1a and Bmpr1b have been inactivated in the neural tube, we demonstrate that BMP signaling contributes to the maturation of glial cells in vivo. At P0, mutant mice exhibited a 25-40% decrease in GFAP+ or S100β+ astrocytes in the cervical spinal cord. The number of oligodendrocyte precursors and the timing of their emergence was unchanged in the mutant mice compared to the normals, however myelin protein expression and mature oligodendrocyte numbers were significantly reduced. These data indicate that BMP signaling promotes the generation of astrocytes and mature, myelinating oligodendrocytes in vivo but does not affect oligodendrocyte precursor development, thus suggesting tight regulation of BMP signaling to ensure proper gliogenesis.

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Maturation-dependent apoptotic cell death of oligodendrocytes in myelin-deficient rats

Cited by 32 publications

References 66 publications

Elevated Levels of the Chemokine GRO-1 Correlate with Elevated Oligodendrocyte Progenitor Proliferation in theJimpyMutant

Elevated Levels of the Chemokine GRO-1 Correlate with Elevated Oligodendrocyte Progenitor Proliferation in theJimpyMutant

Genetic Analyses Demonstrate That Bone Morphogenetic Protein Signaling Is Required for Embryonic Cerebellar Development

BMP signaling mutant mice exhibit glial cell maturation defects

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