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Knockdown of Rab7B, But Not of Rab7A, Which Antagonistically Regulates Oligodendroglial Cell Morphological Differentiation, Recovers Tunicamycin-Induced Defective Differentiation in FBD-102b Cells

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Abstract

In the central nervous system (CNS), insulative myelin sheaths are generated from the differentiated plasma membranes of oligodendrocytes (oligodendroglial cells) and surround neuronal axons to achieve saltatory conduction. Despite the functional involvement of myelin sheaths in the CNS, the molecular mechanism by which oligodendroglial cells themselves undergo differentiation of plasma membranes remains unclear. It also remains to be explored whether their signaling mechanisms can be applied to treating diseases of the oligodendroglial cells. Here, we describe that Rab7B of Rab7 subfamily small GTPases negatively regulates oligodendroglial cell morphological differentiation using FBD-102b cells, which are model cells undergoing differentiation of oligodendroglial precursors. Knockdown of Rab7B or Rab7A by the respective specific siRNAs in cells positively or negatively regulated morphological differentiation, respectively. Consistently, these changes were supported by changes on differentiation- and myelination-related structural protein and protein kinase markers. We also found that knockdown of Rab7B has the ability to recover inhibition of morphological differentiation following tunicamycin-induced endoplasmic reticulum (ER) stress, which mimics one of the major molecular pathological causes of hereditary hypomyelinating disorders in oligodendroglial cells, such as Pelizaeus-Merzbacher disease (PMD). These results suggest that the respective molecules among very close Rab7 homologues exhibit differential roles in morphological differentiation and that knocking down Rab7B can recover defective differentiating phenotypes under ER stress, thereby adding Rab7B to the list of molecular therapeutic cues taking advantage of signaling mechanisms for oligodendroglial diseases like PMD.

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Data Availability

The data that supports the findings of this study is available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Drs. Takako Morimoto and Yoichi Seki (Tokyo University of Pharmacy and Life Sciences) for the insightful comments they provided throughout this study.

Funding

This work was supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT) and Grants-in-Aid for Medical Scientific Research from the Japanese Ministry of Health, Labor and Welfare (MHLW). This work was also supported by Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Agency (JST), Takeda Science Foundation, Daiichi Sankyo Science Foundation, and Mitsubishi Tanabe Science Foundation.

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Authors and Affiliations

  1. Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan

    Nana Fukushima, Remina Shirai, Takanari Sato, Sayumi Nakamura, Arisa Ochiai, Yuki Miyamoto & Junji Yamauchi

  2. Department of Pharmacology, National Research Institute for Child Health and Development, 2-10-1, Setagaya, Tokyo, 157-8535, Japan

    Yuki Miyamoto & Junji Yamauchi

  3. Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo, 156-8506, Japan

    Junji Yamauchi

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  1. Nana Fukushima
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  2. Remina Shirai
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  5. Arisa Ochiai
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Contributions

Junji Yamauchi and Yuki Miyamoto designed this study, wrote this manuscript, and edited it. Nana Fukushima, Remina Shirai, Takanari Sato, Sayumi Nakamura, and Arisa Ochiai performed the experiments. Nana Fukushima and Remina Shirai performed the statistical analyses.

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Correspondence to Yuki Miyamoto or Junji Yamauchi.

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Fukushima, N., Shirai, R., Sato, T. et al. Knockdown of Rab7B, But Not of Rab7A, Which Antagonistically Regulates Oligodendroglial Cell Morphological Differentiation, Recovers Tunicamycin-Induced Defective Differentiation in FBD-102b Cells. J Mol Neurosci 73, 363–374 (2023). https://doi.org/10.1007/s12031-023-02117-y

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