MECP2 Mutation Interrupts Nucleolin–mTOR–P70S6K Signaling in Rett Syndrome Patients
Rett syndrome (RTT) is a severe and rare neurological disorder that is caused by mutations in the X-linked MECP2 (methyl CpG-binding protein 2) gene. MeCP2 protein is an important epigenetic factor in the brain and in neurons. In Mecp2-deficient neurons, nucleoli structures are compromised. Nucleoli...
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Frontiers Media S.A.
2018-12-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2018.00635/full |
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| author | Carl O. Olson Shervin Pejhan Daniel Kroft Kimia Sheikholeslami Kimia Sheikholeslami David Fuss Marjorie Buist Annan Ali Sher Marc R. Del Bigio Yehezkel Sztainberg Victoria Mok Siu Lee Cyn Ang Marianne Sabourin-Felix Tom Moss Mojgan Rastegar |
| author_facet | Carl O. Olson Shervin Pejhan Daniel Kroft Kimia Sheikholeslami Kimia Sheikholeslami David Fuss Marjorie Buist Annan Ali Sher Marc R. Del Bigio Yehezkel Sztainberg Victoria Mok Siu Lee Cyn Ang Marianne Sabourin-Felix Tom Moss Mojgan Rastegar |
| author_sort | Carl O. Olson |
| collection | DOAJ |
| description | Rett syndrome (RTT) is a severe and rare neurological disorder that is caused by mutations in the X-linked MECP2 (methyl CpG-binding protein 2) gene. MeCP2 protein is an important epigenetic factor in the brain and in neurons. In Mecp2-deficient neurons, nucleoli structures are compromised. Nucleoli are sites of active ribosomal RNA (rRNA) transcription and maturation, a process mainly controlled by nucleolin and mechanistic target of rapamycin (mTOR)–P70S6K signaling. Currently, it is unclear how nucleolin–rRNA–mTOR–P70S6K signaling from RTT cellular model systems translates into human RTT brain. Here, we studied the components of nucleolin–rRNA–mTOR–P70S6K signaling in the brain of RTT patients with common T158M and R255X mutations. Immunohistochemical examination of T158M brain showed disturbed nucleolin subcellular localization, which was absent in Mecp2-deficient homozygous male or heterozygote female mice, compared to wild type (WT). We confirmed by Western blot analysis that nucleolin protein levels are altered in RTT brain, but not in Mecp2-deficient mice. Further, we studied the expression of rRNA transcripts in Mecp2-deficient mice and RTT patients, as downstream molecules that are controlled by nucleolin. By data mining of published ChIP-seq studies, we showed MeCP2-binding at the multi-copy rRNA genes in the mouse brain, suggesting that rRNA might be a direct MeCP2 target gene. Additionally, we observed compromised mTOR–P70S6K signaling in the human RTT brain, a molecular pathway that is upstream of rRNA–nucleolin molecular conduits. RTT patients showed significantly higher phosphorylation of active mTORC1 or mTORC2 complexes compared to age- and sex-matched controls. Correlational analysis of mTORC1/2–P70S6K signaling pathway identified multiple points of deviation from the control tissues that may result in abnormal ribosome biogenesis in RTT brain. To our knowledge, this is the first report of deregulated nucleolin–rRNA–mTOR–P70S6K signaling in the human RTT brain. Our results provide important insight toward understanding the molecular properties of human RTT brain. |
| first_indexed | 2024-04-13T14:59:29Z |
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| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-13T14:59:29Z |
| publishDate | 2018-12-01 |
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| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-d5ec5417e1f1402e90cc3f8fa5bb1e262022-12-22T02:42:20ZengFrontiers Media S.A.Frontiers in Genetics1664-80212018-12-01910.3389/fgene.2018.00635391424MECP2 Mutation Interrupts Nucleolin–mTOR–P70S6K Signaling in Rett Syndrome PatientsCarl O. Olson0Shervin Pejhan1Daniel Kroft2Kimia Sheikholeslami3Kimia Sheikholeslami4David Fuss5Marjorie Buist6Annan Ali Sher7Marc R. Del Bigio8Yehezkel Sztainberg9Victoria Mok Siu10Lee Cyn Ang11Marianne Sabourin-Felix12Tom Moss13Mojgan Rastegar14Regenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, CanadaRegenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, CanadaRegenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, CanadaRegenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, CanadaFaculty of Medicine, University of Toronto, Toronto, ON, CanadaRegenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, CanadaRegenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, CanadaRegenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, CanadaDepartment of Pathology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, CanadaDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United StatesDivision of Medical Genetics, Department of Paediatrics, Schulich School of Medicine, Western University, London, ON, CanadaDepartment of Pathology, Schulich School of Medicine and Dentistry, Western University, London, ON, CanadaCancer Division of the Quebec University Hospital Research Centre, Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, Quebec City, QC, CanadaCancer Division of the Quebec University Hospital Research Centre, Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, Quebec City, QC, CanadaRegenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, CanadaRett syndrome (RTT) is a severe and rare neurological disorder that is caused by mutations in the X-linked MECP2 (methyl CpG-binding protein 2) gene. MeCP2 protein is an important epigenetic factor in the brain and in neurons. In Mecp2-deficient neurons, nucleoli structures are compromised. Nucleoli are sites of active ribosomal RNA (rRNA) transcription and maturation, a process mainly controlled by nucleolin and mechanistic target of rapamycin (mTOR)–P70S6K signaling. Currently, it is unclear how nucleolin–rRNA–mTOR–P70S6K signaling from RTT cellular model systems translates into human RTT brain. Here, we studied the components of nucleolin–rRNA–mTOR–P70S6K signaling in the brain of RTT patients with common T158M and R255X mutations. Immunohistochemical examination of T158M brain showed disturbed nucleolin subcellular localization, which was absent in Mecp2-deficient homozygous male or heterozygote female mice, compared to wild type (WT). We confirmed by Western blot analysis that nucleolin protein levels are altered in RTT brain, but not in Mecp2-deficient mice. Further, we studied the expression of rRNA transcripts in Mecp2-deficient mice and RTT patients, as downstream molecules that are controlled by nucleolin. By data mining of published ChIP-seq studies, we showed MeCP2-binding at the multi-copy rRNA genes in the mouse brain, suggesting that rRNA might be a direct MeCP2 target gene. Additionally, we observed compromised mTOR–P70S6K signaling in the human RTT brain, a molecular pathway that is upstream of rRNA–nucleolin molecular conduits. RTT patients showed significantly higher phosphorylation of active mTORC1 or mTORC2 complexes compared to age- and sex-matched controls. Correlational analysis of mTORC1/2–P70S6K signaling pathway identified multiple points of deviation from the control tissues that may result in abnormal ribosome biogenesis in RTT brain. To our knowledge, this is the first report of deregulated nucleolin–rRNA–mTOR–P70S6K signaling in the human RTT brain. Our results provide important insight toward understanding the molecular properties of human RTT brain.https://www.frontiersin.org/article/10.3389/fgene.2018.00635/fullMECP2 mutationsRett syndromehuman brain tissuesDNA methylationribosome biogenesismTOR |
| spellingShingle | Carl O. Olson Shervin Pejhan Daniel Kroft Kimia Sheikholeslami Kimia Sheikholeslami David Fuss Marjorie Buist Annan Ali Sher Marc R. Del Bigio Yehezkel Sztainberg Victoria Mok Siu Lee Cyn Ang Marianne Sabourin-Felix Tom Moss Mojgan Rastegar MECP2 Mutation Interrupts Nucleolin–mTOR–P70S6K Signaling in Rett Syndrome Patients Frontiers in Genetics MECP2 mutations Rett syndrome human brain tissues DNA methylation ribosome biogenesis mTOR |
| title | MECP2 Mutation Interrupts Nucleolin–mTOR–P70S6K Signaling in Rett Syndrome Patients |
| title_full | MECP2 Mutation Interrupts Nucleolin–mTOR–P70S6K Signaling in Rett Syndrome Patients |
| title_fullStr | MECP2 Mutation Interrupts Nucleolin–mTOR–P70S6K Signaling in Rett Syndrome Patients |
| title_full_unstemmed | MECP2 Mutation Interrupts Nucleolin–mTOR–P70S6K Signaling in Rett Syndrome Patients |
| title_short | MECP2 Mutation Interrupts Nucleolin–mTOR–P70S6K Signaling in Rett Syndrome Patients |
| title_sort | mecp2 mutation interrupts nucleolin mtor p70s6k signaling in rett syndrome patients |
| topic | MECP2 mutations Rett syndrome human brain tissues DNA methylation ribosome biogenesis mTOR |
| url | https://www.frontiersin.org/article/10.3389/fgene.2018.00635/full |
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