title: Histological detection of dynamic glial responses in the dysmyelinating Tabby-jimpy mutant brain.
abstract: 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.
authors.affiliation: Division of Neurobiology and Anatomy, Niigata University, Niigata, 951-8510, Japan.|Department of Otolaryngology Head and Neck Surgery, Niigata University, Niigata, 951-8510, Japan.
authors.forename: Masanao
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Division of Neurobiology and Anatomy, Niigata University, Niigata, 951-8510, Japan.
authors.forename: M Ibrahim
authors.initials: MI
authors.lastname: Hossain
authors.affiliation: Division of Neurobiology and Anatomy, Niigata University, Niigata, 951-8510, Japan.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Neurobiology and Anatomy, Niigata University, Niigata, 951-8510, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Horie
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, 444-8787, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ikenaka
authors.affiliation: Department of Otolaryngology Head and Neck Surgery, Niigata University, Niigata, 951-8510, Japan.
authors.forename: Arata
authors.initials: A
authors.lastname: Horii
authors.affiliation: Division of Neurobiology and Anatomy, Niigata University, Niigata, 951-8510, Japan. takebaya@med.niigata-u.ac.jp.
authors.forename: Hirohide
authors.identifier: http://orcid.org/0000-0003-4493-6604
authors.initials: H
authors.lastname: Takebayashi
mesh_terms: D000818:Animals; D016375:Antisense Elements (Genetics); D001921:Brain / Q000166:cytology* / Q000473:pathology*; D016923:Cell Death; D003711:Demyelinating Diseases / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D005260:Female; D006896:Hydroxyethylrutoside; D008297:Male; D008817:Mice, Mutant Strains; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014960:X Chromosome / Q000235:genetics
chemical_list: D016375:Antisense Elements (Genetics); C497250:Ddit3 protein, mouse; D006896:Hydroxyethylrutoside; D018991:Myelin Proteolipid Protein; C047516:Plp1 protein, mouse; D012333:RNA, Messenger; D051742:Transcription Factor CHOP
keywords: CHOP; Dysmyelination; ER stress; Oligodendrocyte; Proteolipid protein