PMID- 30619462 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20201001 IS - 1664-8021 (Print) IS - 1664-8021 (Electronic) IS - 1664-8021 (Linking) VI - 9 DP - 2018 TI - MECP2 Mutation Interrupts Nucleolin-mTOR-P70S6K Signaling in Rett Syndrome Patients. PG - 635 LID - 10.3389/fgene.2018.00635 [doi] LID - 635 AB - 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. FAU - Olson, Carl O AU - Olson CO AD - Regenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. FAU - Pejhan, Shervin AU - Pejhan S AD - Regenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. FAU - Kroft, Daniel AU - Kroft D AD - Regenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. FAU - Sheikholeslami, Kimia AU - Sheikholeslami K AD - Regenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. AD - Faculty of Medicine, University of Toronto, Toronto, ON, Canada. FAU - Fuss, David AU - Fuss D AD - Regenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. FAU - Buist, Marjorie AU - Buist M AD - Regenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. FAU - Ali Sher, Annan AU - Ali Sher A AD - Regenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. FAU - Del Bigio, Marc R AU - Del Bigio MR AD - Department of Pathology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. FAU - Sztainberg, Yehezkel AU - Sztainberg Y AD - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States. FAU - Siu, Victoria Mok AU - Siu VM AD - Division of Medical Genetics, Department of Paediatrics, Schulich School of Medicine, Western University, London, ON, Canada. FAU - Ang, Lee Cyn AU - Ang LC AD - Department of Pathology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. FAU - Sabourin-Felix, Marianne AU - Sabourin-Felix M AD - Cancer Division of the Quebec University Hospital Research Centre, Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, Quebec City, QC, Canada. FAU - Moss, Tom AU - Moss T AD - Cancer Division of the Quebec University Hospital Research Centre, Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, Quebec City, QC, Canada. FAU - Rastegar, Mojgan AU - Rastegar M AD - Regenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. LA - eng PT - Journal Article DEP - 20181219 PL - Switzerland TA - Front Genet JT - Frontiers in genetics JID - 101560621 PMC - PMC6305968 OTO - NOTNLM OT - DNA methylation OT - MECP2 mutations OT - Rett syndrome OT - human brain tissues OT - mTOR OT - nucleolin OT - protein translation OT - ribosome biogenesis EDAT- 2019/01/09 06:00 MHDA- 2019/01/09 06:01 PMCR- 2018/12/19 CRDT- 2019/01/09 06:00 PHST- 2018/06/01 00:00 [received] PHST- 2018/11/27 00:00 [accepted] PHST- 2019/01/09 06:00 [entrez] PHST- 2019/01/09 06:00 [pubmed] PHST- 2019/01/09 06:01 [medline] PHST- 2018/12/19 00:00 [pmc-release] AID - 10.3389/fgene.2018.00635 [doi] PST - epublish SO - Front Genet. 2018 Dec 19;9:635. doi: 10.3389/fgene.2018.00635. eCollection 2018.