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

Abstract

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.

Neuroprotection and Remyelination after Autoimmune Demyelination in Mice that Inducibly Overexpress CXCL1

“…47 Moreover, elevated levels of CXCL1 in the jimpy mutant correlated with increased proliferation of NG2 ϩ oligodendrocyte progenitors. 64 CXCL1 has also been shown to provide a migratory stop signal for oligodendrocyte precursor cells, thus influencing positioning of cells of the oligodendrocyte lineage during CNS development. 48 Together with our earlier results that showed CXCR2 ϩ oligodendrocytes closely associated with CXCL1 ϩ hypertrophic astrocytes at the edge of MS lesions, 24,55 the current findings suggest that CXCL1/CXCR2-mediated signals might lead to the accumulation or recruitment of oligodendrocytes at the lesion margin and potentially promote repair.…”

RANTES-mediated Chemokine Transcription in Astrocytes Involves Activation and Translocation of p90 Ribosomal S6 Protein Kinase (RSK)

“…KC and the structurally related chemokine MIP-2 may contribute to inflammation by recruiting leukocytes to the CNS, and they may also participate in the subsequent repair processes by promoting the growth of oligodendrocytes (46,47). TNF-␣ is a multipotential cytokine involved in microglial activation, neuronal death, and immune regulation (48,49).…”

The Generation of Definitive Neural Stem Cells from PiggyBac Transposon-Induced Pluripotent Stem Cells Can Be Enhanced by Induction of the NOTCH Signaling Pathway

“…The instructive niche of the dysmyelinated CNS of Shiverer mice promotes adult tissue-derived NSCs and ES-dNSCs to yield primarily myelinating oligodendrocytes even though their in vitro profile suggested astrocytic differentiation [28,48,51]. For example, through factors, such as GRO-1 or neuregulin, NG2-positive oligodendrocytes may be creating an environment that preferentially direct dNSCs to an oligodendrocytic lineage [52,53]. However, induction of the NOTCH pathway has been implicated in promoting an astrocytic differentiation [54].…”