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Hotair and Malat1 Long Noncoding RNAs Regulate Bdnf Expression and Oligodendrocyte Precursor Cell Differentiation

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Abstract

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophins family with well-known roles in neural development, differentiation, survival, and synaptic plasticity; however, it has not been explained thoroughly how the expression of this critical gene is regulated. To reveal some aspects of Bdnf gene regulation, here it was explored whether metastasis-associated lung adenocarcinoma transcript 1 (Malat1) and HOX transcript antisense RNA (Hotair) lncRNAs play roles in the regulation of Bdnf expression level, the effect of fingolimod treatment on downstream pathways, and oligodendrocyte precursor cell (OPC) maturation. First, in rat primary glial culture, the effect of Hotair and Malat1 was investigated on Bdnf expression using downregulation by specific DNAzymes. Then, immunostaining and RT-qPCR assays were employed to assess the functions of fingolimod and lncRNAs on OPC maturation. The results demonstrated that Bdnf was significantly correlated to Hotair and Malat1 lncRNAs in glial cells. Also, a strong correlation was observed between these two lncRNAs in glial culture and isolated OPCs. Fingolimod treatment coordinated lncRNAs' role on Bdnf expression in glial cells and enhanced OPC myelination three times compared to control. Furthermore, results suggested that Malat1 may have a role in the last stages of the intrinsic oligodendrocyte (OL) myelination regardless of fingolimod treatment. As BDNF is involved in brain development, survival, and functions, understanding the regulatory mechanism behind BDNF expression leads to a better comprehension of the pathogenesis of the neurodegenerative disorder and designing more effective treatments.

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Data availability

The data that support the findings of this study are available on request from the corresponding authors.

Code availability

Not applicable.

Abbreviations

BBB:

Blood–brain barrier

BDNF:

Brain-derived neurotrophic factor

bFGF:

Basic fibroblast growth factor

ceRNA:

Competitive endogenous RN

CNS:

Central nervous system

EGF:

Epidermal growth factor

HOTAIR:

HOX transcript antisense RNA

IGF-1:

Insulin-like growth factor 1

lncRNA:

Long noncoding RNAs

MALAT1:

Metastasis-associated lung adenocarcinoma transcript 1

MREs:

MicroRNA-binding sites

OL:

Oligodendrocyte

OPC:

Oligodendrocyte precursor cell

PDGF:

Platelet-derived growth factor

PLL:

Poly-L-lysine

T3:

Triiodo-L-thyronine

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Acknowledgements

The authors thank Javad Mirnajafi-Zadeh for providing rat pups for this study. We also thank the funding source for their support.

Funding

This work was supported by the Iran National Science Foundation and the Department of Research Affairs of Tarbiat Modares University.

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Authors and Affiliations

  1. Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, P.O. Box: 14115-154, Iran

    Fatemeh Khani-Habibabadi & Mehrdad Behmanesh

  2. Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, P.O. Box: P.O. Box 14115-331, Iran

    Leila Zare & Mohammad Javan

  3. MS Research Center, Neuroscience Institute, Tehran University of Medical Science, Tehran, Iran

    Mohammad Ali Sahraian

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  1. Fatemeh Khani-Habibabadi
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  2. Leila Zare
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  3. Mohammad Ali Sahraian
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  4. Mohammad Javan
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  5. Mehrdad Behmanesh
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Fatemeh Khani-Habibabadi, Mehrdad Behmanesh, Leila Zare, and Mohammad Javan. The draft of the manuscript was written by Fatemeh Khani-Habibabadi, and it was corrected by Mehrdad Behmanesh. All authors read and approved the final manuscript.

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Correspondence to Mohammad Javan or Mehrdad Behmanesh.

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The procedures of this research were approved by the ethics community of Tarbiat Modares University (ID: IR.TMU.REC.1396.607).

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Khani-Habibabadi, F., Zare, L., Sahraian, M.A. et al. Hotair and Malat1 Long Noncoding RNAs Regulate Bdnf Expression and Oligodendrocyte Precursor Cell Differentiation. Mol Neurobiol 59, 4209–4222 (2022). https://doi.org/10.1007/s12035-022-02844-0

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