Mice lacking BCAS1, a novel myelin‐associated protein, display hypomyelination, schizophrenia‐like abnormal behaviors, and upregulation of inflammatory genes in the brain

Ishimoto, Tetsuya; Ninomiya, K.; Inoue, Ran; Koike, Masato; Uchiyama, Yasuo; Mori, Hisashi

doi:10.1002/glia.23129

Cited by 43 publications

(34 citation statements)

References 59 publications

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“…BCAS1 was originally identified as mRNA amplified in human cancer cell lines (17), but recent transcriptome studies have shown that it is also highly expressed in the brain and, more specifically, in oligodendrocytes (18). The function of BCAS1 is unknown, but there is evidence that it interacts with the dynein light chain (19) and is required for brain function because its absence results in reduced anxiety and schizophrenia-like behavioral abnormalities in mice (20).…”

Section: Introductionmentioning

confidence: 99%

BCAS1 expression defines a population of early myelinating oligodendrocytes in multiple sclerosis lesions

et al. 2017

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Section: Introductionmentioning

confidence: 99%

BCAS1 expression defines a population of early myelinating oligodendrocytes in multiple sclerosis lesions

et al. 2017

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“…This help to explain why some ULK4 patients present severe learning difficulty and language delay (Liu, Guan, Shen, Flinter, et al, ). Schizophrenia‐associated myelin‐related genes including CNP , ERBB3 , GSN , MAL , MAG (Jungerius et al, ), and Bcas1 gene which display hypomyelination and schizophrenia‐like behaviours in mutants (Ishimoto et al, ) are all downregulated in Ulk4 hypomorph mice.…”

Section: Discussionmentioning

confidence: 99%

“…Several myelin‐related genes, including CNP , ERBB3 , GSN , MAL , MAG and TF , are differentially expressed in schizophrenia post‐mortem brain tissue compared to unaffected controls (Jungerius et al, ). Mice lacking Bcas1 , a novel myelin‐associated protein interacting with F‐actin and the dynein light chain, exhibited schizophrenia‐like abnormal behavior, upregulated inflammation and hypomyelination (Ishimoto et al, ).…”

Section: Introductionmentioning

confidence: 99%

Ulk4 deficiency leads to hypomyelination in mice

Liu

Guan

et al. 2017

Glia

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Brain nerve fibers are insulated by myelin which is produced by oligodendrocytes. Defects in myelination are increasingly recognized as a common pathology underlying neuropsychiatric and neurodevelopmental disorders, which are associated with deletions of the Unc-51-like kinase 4 (ULK4) gene. Key transcription factors have been identified for oligodendrogenesis, but little is known about their associated regulators. Here we report that Ulk4 acts as a key regulator of myelination. Myelination is reduced by half in the Ulk4 tm1a/tm1a hypomorph brain, whereas expression of axonal marker genes Tubb3, Nefh, Nefl and Nefm remains unaltered. Transcriptome analyses reveal that 8 (Gfap, Mbp, Mobp, Plp1, Slc1a2, Ttr, Cnp, Scd2) of the 10 most significantly altered genes in the Ulk4 tm1a/tm1a brain are myelination-related. Ulk4 is co-expressed in Olig2 1 (pan-oligodendrocyte marker) and CC1 1 (mature myelinated oligodendrocyte marker) cells during postnatal development.Major oligodendrogeneic transcription factors, including Olig2, Olig1, Myrf, Sox10, Sox8, Sox6, Sox17, Nkx2-2, Nkx6-2 and Carhsp1, are significantly downregulated in the mutants. mRNA transcripts enriched in oligodendrocyte progenitor cells (OPCs), the newly formed oligodendrocytes (NFOs) and myelinating oligodendrocytes (MOs), are significantly attenuated. Expression of stage-specific oligodendrocyte factors including Cspg4, Sox17, Nfasc, Enpp6, Sirt2, Cnp, Plp1, Mbp, Ugt8, Mag and Mog are markedly decreased. Indirect effects of axon caliber and neuroinflammation may also contribute to the hypomyelination, as Ulk4 mutants display smaller axons and increased neuroinflammation. This is the first evidence demonstrating that ULK4 is a crucial regulator of myelination, and ULK4 may therefore become a novel therapeutic target for hypomyelination diseases. K E Y W O R D Shypomyelination, knockout mice, oligodendrogenesis, Ulk4, white matter integrity

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“…7A. Based on enrichment analysis for DEGs with GO terms ( Supplementary Table 1) and literature (Han et al, 2012;Dashzeveg et al, 2014;Das et al, 2015;Ishimoto et al, 2017), DEGs were overrepresented in the categories 'Immune system', 'Development and proliferation', 'Extracellular matrix', 'RNA polymerase II transcription' and 'P53 mediated signaling' (Fig. 7B), suggesting these processes are differentially regulated between VWM and wt CNTF-mAstro.…”

Section: Mipsc-based Models Show Selective Involvement Of Astrocytic mentioning

confidence: 97%

Human and mouse iPSC-derived astrocyte subtypes reveal vulnerability in Vanishing White Matter

Leferink

Dooves

Hillen

et al. 2019

Preprint

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Astrocytes gained attention as important players in neurological disease, including a number of leukodystrophies. Several studies explored the generation of induced pluripotent stem cell-derived astrocytes for drug screening and regenerative studies. Developing robust models of patient induced pluripotent stem cells is challenged by high variability due to diverse genetic backgrounds and long-term culture procedures. While human models are of special interest, mouse-based models have the advantage that for them these issues are less pronounced. Here we present astrocyte differentiation protocols for both human and mouse induced pluripotent stem cells to specifically induce grey and white matter astrocytes. Both subtypes expressed astrocyte-associated markers, had typical astrocyte morphologies, and gave a reactive response to stress. Importantly, the grey and white matter-like astrocytes differed in size, complexity of processes, and expression profile, conform primary grey and white matter astrocytes. The newly presented mouse and human stem cell-based models for the leukodystrophy Vanishing White Matter replicated earlier findings, such as increased proliferation, decreased OPC maturation and modulation by hyaluronidase. We studied intrinsic astrocyte subtype vulnerability in Vanishing White Matter in both human and mouse cells. Oligodendrocyte maturation was specifically inhibited in cultures with Vanishing WhiteMatter white matter-like astrocytes. By performing RNA sequencing, we found more differentially regulated genes in the white than in the grey matter-like astrocytes. Human and mouse astrocytes showed the same affected pathways, although human white matter-like astrocytes presented human-specific disease mechanisms involved in Vanishing White Matter. Using both human and mouse induced pluripotent stem cells, our study presents protocols to generate white and grey matter-like astrocytes, and shows astrocyte subtypespecific defects in Vanishing White Matter. While mouse induced pluripotent stem cell-based cultures may be less suitable to mimic human astrocyte subtype-or patient-specific changes, they might more robustly represent disease mutation-related cellular phenotypes as the cells are derived from inbred mice and the protocols are faster. The presented models give new tools to generate astrocyte subtypes for in vitro disease modeling and in vivo regenerative applications.

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Mice lacking BCAS1, a novel myelin‐associated protein, display hypomyelination, schizophrenia‐like abnormal behaviors, and upregulation of inflammatory genes in the brain

Cited by 43 publications

References 59 publications

BCAS1 expression defines a population of early myelinating oligodendrocytes in multiple sclerosis lesions

BCAS1 expression defines a population of early myelinating oligodendrocytes in multiple sclerosis lesions

Ulk4 deficiency leads to hypomyelination in mice

Human and mouse iPSC-derived astrocyte subtypes reveal vulnerability in Vanishing White Matter

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