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Differential Expression and Regulation of Brain-Derived Neurotrophic Factor (BDNF) mRNA Isoforms in Brain Cells from Mecp2308/y Mouse Model

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Abstract

Rett syndrome (RTT) is a severe neurodevelopmental disease caused by mutations in methyl-CpG-binding protein 2 (MECP2), which encodes a transcriptional modulator of many genes including BDNF. BDNF comprises nine distinct promoter regions, each triggering the expression of a specific transcript. The role of this diversity of transcripts remains unknown. MeCP2 being highly expressed in neurons, RTT was initially considered as a neuronal disease. However, recent studies have shown that MeCP2 was also expressed in astrocytes. Though several studies explored Bdnf IV expression in Mecp2-deficient mice, the differential expression of Bdnf isoforms in Mecp2-deficient neurons and astrocytes was never studied. By using TaqMan technology and a mouse model expressing a truncated Mecp2 (Mecp2308/y), we firstly showed in neurons that Bdnf transcripts containing exon I, IIb, IIc, IV, and VI are prominently expressed, whereas in astrocytes, Bdnf transcript containing exon VI is preferentially expressed, suggesting a specific regulation of Bdnf expression at the cellular level. Secondly, we confirmed the repressive role of Mecp2 only on the expression of Bdnf VI in neurons. Our data suggested that the truncated Mecp2 protein maintains its function on Bdnf expression regulation in neurons and in astrocytes. Interestingly, we observed that Bdnf transcripts (I and IXA), regulated by neural activity induced by bicuculline in Mecp2308/y neurons, were not affected by histone deacetylase inhibition. In contrast, Bdnf transcripts (IIb, IIc, and VI), regulated by histone deacetylation, were not affected by bicuculline treatment in wild-type and Mecp2308/y neurons. All these results reflect the complexity of regulation of Bdnf gene.

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Acknowledgments

This study was supported by grants from Fondation Jerome Lejeune, and Labex Who I Am.

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Correspondence to Thierry Bienvenu.

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Audrey Rousseaud and Chloé Delépine contributed equally to this work.

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Figure 1S

Relative expression level of Arc from WT hippocampal and cortical neurons: real-time RT-quantitative PCR analysis showing the relative changes of Arc after 1 h exposure to bicuculline. Bars represent means +/−SEM. HPC means hippocampal, CTX means cortical. (PDF 56 kb)

Figure 2S

Relative expression level of Gad1 from WT astrocytes and hippocampal and cortical neurons. Bars represent means +/−SEM. HPC means hippocampal, CTX means cortical. (PDF 4 kb)

Figure 3S

Immunostaining with rabbit anti-γ-aminobutyric acid (GABA) antibody (red). Nuclei have been visualized by DAPI staining (blue). (PDF 778 kb)

Figure 4S

Effect of bicuculline (bicu) and trichostatin A (TSA) on Bdnf transcription in wild-type (WT) and Mecp2308/y cortical neurons: real-time RT-quantitative PCR analysis showing the relative changes of Bdnf transcripts IIc and VI after 1 and 19-h exposure to bicuculline and trichostatin A, respectively. Ctrl means control as untreated cells. Bars represent means +/−SEM. Statistical analysis was determined by analysis of variance (ANOVA). * indicates p < 0.05. (PDF 7 kb)

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Rousseaud, A., Delépine, C., Nectoux, J. et al. Differential Expression and Regulation of Brain-Derived Neurotrophic Factor (BDNF) mRNA Isoforms in Brain Cells from Mecp2308/y Mouse Model. J Mol Neurosci 56, 758–767 (2015). https://doi.org/10.1007/s12031-014-0487-0

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  • DOI: https://doi.org/10.1007/s12031-014-0487-0

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