Histological detection of dynamic glial responses in the dysmyelinating Tabby-jimpy mutant brain
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Oligodendrocytes (OLs) are glial cells that form myelin sheaths surrounding the axons in the central nervous system (CNS). Jimpy (jp) mutant mice are dysmyelinating disease models that show developmental abnormalities in myelinated OLs in the CNS. The causative gene in jp mice is the proteolipid protein (PLP) located on the X chromosome. Mutations in the jp allele result in exon 5 skipping and expression of abnormal PLP containing a C-terminal frame shift. Many lines of evidence suggest that abnormal PLP in OLs results in endoplasmic reticulum (ER) stress and cell death. To histologically detect glial responses in the jp mutant brain, we performed staining with lineage-specific markers. Using OL markers and OL progenitor cell marker staining, we identified reduced numbers of OL lineage cells in the jp mutant brain. Nuclear staining of the transcription factor Olig1 was observed in the Tabby-jp brain, whereas cytoplasmic Olig1 staining was observed in the wild-type brain at postnatal day 21, suggesting that active myelination was present in the mutant brain. Many microglial cells with activated morphology and intensive staining of CD11b microglia marker were observed in the internal capsule of the mutant brain, a region of white matter containing residual OLs. Activated astrocytes with high glial fibrillary acidic protein-immunoreactivity were also mainly observed in white matter. Finally, we performed in situ hybridization using C/EBP homologous protein (CHOP) antisense probes to detect ER stressed cells. CHOP mRNA was strongly expressed in residual OLs in the Tabby-jp mutant mice at postnatal stages. These data show that microglia and astrocytes exhibit dynamic glial activation in response to cell death of OLs during Tabby-jp pathogenesis, and that CHOP antisense probes may be a good marker for the detection of ER-stressed OLs in jp mutant mice.
KeywordsOligodendrocyte Dysmyelination Proteolipid protein ER stress CHOP
This study was supported by research grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; Grant-in-Aid for Scientific Research (B) (15H04667, H.T.), Grant-in-Aid for Scientific Research on Innovative Areas, “Glial assembly” (25117007, H.T.) and Grant-in-Aid for Exploratory Research (16K15168, H.T.); and a Grant from the Niigata University Kyowakai Society (M.I.). We thank Dr. Tetsushi Kagawa for PLP plasmid; Dr. Yukiko Mori and Ms. Satoko Yamagiwa for technical assistance; Dr. Yoshihide Yamaguchi, Dr. Mari Tada, Dr. Akiyoshi Kakita, Dr. Kazunori Imaizumi, Dr. Takashi Kudo for discussion; all Takebayashi laboratory members, especially Dr. Norihisa Bizen and Dr. Masato Yano, for providing input and advice, and Dr. Sugata Takahashi for continual support.
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Conflict of interest
The authors declare that they have no conflict of interest.
Movie S1 Ta-jp mutant mouse (2 weeks old). One Ta-jp mutant (Ta-jp/Y) and two control littermates (+/Y) at P14. The Ta-jp mutant has smaller body than wild-type mice and shows a shivering phenotype and ataxic gait (MP4 15735 kb)
Movie S2 Ta-jp mutant mouse (3 weeks old). One Ta-jp mutant (Ta-jp/Y) and one control littermate (+/Y) at P21. The Ta-jp mutant has smaller body than wild-type mice and shows shivering phenotype with extended and spastic hindlimbs (MP4 6848 kb)
- Schneider A, Montague P, Griffiths IR, Fanarraga ML, Kennedy PGE, Brophy PJ, Nave K-A (1992) Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene. Nature 358:758–761Google Scholar