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Mecp2 stem cell

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https://www.readbyqxmd.com/read/29563495/neural-stem-cells-from-a-mouse-model-of-rett-syndrome-are-prone-to-senescence-show-reduced-capacity-to-cope-with-genotoxic-stress-and-are-impaired-in-the-differentiation-process
#1
Nicola Alessio, Francesco Riccitiello, Tiziana Squillaro, Stefania Capasso, Stefania Del Gaudio, Giovanni Di Bernardo, Marilena Cipollaro, Mariarosa A B Melone, Gianfranco Peluso, Umberto Galderisi
Several aspects of stem cell life are governed by epigenetic variations, such as DNA methylation, histone modifications, and chromatin remodeling. Epigenetic events are also connected with the impairment of stem cell functions. For example, during senescence, there are significant changes in chromatin organization that alter transcription. The MECP2 protein can bind methylated cytosines and contribute to regulating gene expression at one of the highest hierarchical levels. Researchers are particularly interested in this protein, as up to 90% of Rett syndrome patients have an MECP2 gene mutation...
March 22, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29562294/mecp2-deficiency-promotes-cell-reprogramming-by-stimulating-igf1-akt-mtor-signaling-and-activating-ribosomal-protein-mediated-cell-cycle-gene-translation
#2
Wei Zhang, Guihai Feng, Libin Wang, Fei Teng, Liu Wang, Wei Li, Ying Zhang, Qi Zhou
The generation of induced pluripotent stem cells (iPSCs) offers a great opportunity in research and regenerative medicine. The current poor efficiency and incomplete mechanistic understanding of the reprogramming process hampers the clinical application of iPSCs. MeCP2 connects histone modification and DNA methylation, which are key changes of somatic cell reprogramming. However, the role of MeCP2 in cell reprogramming has not been examined. In this study, we found that MeCP2 deficiency enhanced reprogramming efficiency and stimulated cell proliferation through regulating cell cycle protein expression in the early stage of reprogramming...
March 19, 2018: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/29534967/mitochondrial-dysfunction-in-dopaminergic-neurons-differentiated-from-exfoliated-deciduous-tooth-derived-pulp-stem-cells-of-a-child-with-rett-syndrome
#3
Saki Hirofuji, Yuta Hirofuji, Hiroki Kato, Keiji Masuda, Haruyoshi Yamaza, Hiroshi Sato, Fumiko Takayama, Michiko Torio, Yasunari Sakai, Shouichi Ohga, Tomoaki Taguchi, Kazuaki Nonaka
Rett syndrome is an X-linked neurodevelopmental disorder associated with psychomotor impairments, autonomic dysfunctions and autism. Patients with Rett syndrome have loss-of-function mutations in MECP2, the gene encoding methyl-CpG-binding protein 2 (MeCP2). Abnormal biogenic amine signaling and mitochondrial function have been found in patients with Rett syndrome; however, few studies have analyzed the association between these factors. This study investigated the functional relationships between mitochondria and the neuronal differentiation of the MeCP2-deficient stem cells from the exfoliated deciduous teeth of a child with Rett syndrome...
March 10, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29522154/rsrc1-mutation-affects-intellect-and-behaviour-through-aberrant-splicing-and-transcription-downregulating-igfbp3
#4
Yonatan Perez, Shay Menascu, Idan Cohen, Rotem Kadir, Omer Basha, Zamir Shorer, Hila Romi, Gal Meiri, Tatiana Rabinski, Rivka Ofir, Esti Yeger-Lotem, Ohad S Birk
RSRC1, whose polymorphism is associated with altered brain function in schizophrenia, is a member of the serine and arginine rich-related protein family. Through homozygosity mapping and whole exome sequencing we show that RSRC1 mutation causes an autosomal recessive syndrome of intellectual disability, aberrant behaviour, hypotonia and mild facial dysmorphism with normal brain MRI. Further, we show that RSRC1 is ubiquitously expressed, and that the RSRC1 mutation triggers nonsense-mediated mRNA decay of the RSRC1 transcript in patients' fibroblasts...
April 1, 2018: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29351579/lack-of-methyl-cpg-binding-protein-2-mecp2-affects-cell-fate-refinement-during-embryonic-cortical-development
#5
Clementina Cobolli Gigli, Linda Scaramuzza, Marco De Simone, Riccardo L Rossi, Davide Pozzi, Massimiliano Pagani, Nicoletta Landsberger, Francesco Bedogni
During differentiation, neurons progressively restrict their fate repressing the expression of specific genes. Here we describe the involvement in such developmental steps of the methyl-CpG binding protein 2 (MeCP2), an epigenetic factor that participates to chromatin folding and transcriptional regulation. We previously reported that, due to transcriptional impairments, the maturation of Mecp2 null neurons is delayed. To evaluate whether this could stem from altered progenitors proliferation and differentiation, we investigated whether lack of Mecp2 affects these features both in vitro and in vivo...
January 17, 2018: Cerebral Cortex
https://www.readbyqxmd.com/read/29246895/mirna-22-is-a-novel-mediator-of-vascular-smooth-muscle-cell-phenotypic-modulation-and-neointima-formation
#6
Feng Yang, Qishan Chen, Shiping He, Mei Yang, Eithne Margaret Maguire, Weiwei An, Tayyab Adeel Afzal, Le Anh Luong, Li Zhang, Qingzhong Xiao
Background -MicroRNA-22 (miR-22) has recently been reported to play a regulatory role during vascular smooth muscle cell (VSMC) differentiation from stem cells, but little is known about its target genes and related pathways in mature VSMC phenotypic modulation or its clinical implication in neointima formation following vascular injury. Methods -We applied wire-injury mouse model as well as local delivery of AgomiR-22 or miR-22 inhibitor to explore the therapeutic potential of miR-22 in vascular diseases. Furthermore, normal and diseased human femoral arteries were harvested and various in vivo , ex vivo , and in vitro models of VSMC phenotype switching were conducted to examine miR-22 expression during VSMC phenotype switching...
December 15, 2017: Circulation
https://www.readbyqxmd.com/read/29050935/the-l1-adhesion-molecule-normalizes-neuritogenesis-in-rett-syndrome-derived-neural-precursor-cells
#7
Myungsik Yoo, Cassiano Carromeu, Ohyoon Kwon, Alysson Muotri, Melitta Schachner
Therapeutic intervention is an important need in ameliorating the severe consequences of Rett Syndrome (RTT), a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein-2 (MeCP2). Following previously observed morphological defects in induced pluripotent stem cell (iPSC)-derived neurons obtained from female RTT patients, we hypothesized that transfection with the L1 cell adhesion molecule (L1) could contribute to normalizing a pathological male cell system bearing a nonsense mutation of MeCP2...
December 16, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28523538/mecp2-a-modulator-of-neuronal-chromatin-organization-involved-in-rett-syndrome
#8
REVIEW
Alexia Martínez de Paz, Juan Ausió
From an epigenetic perspective, the genomic chromatin organization of neurons exhibits unique features when compared to somatic cells. Methyl CpG binding protein 2 (MeCP2), through its ability to bind to methylated DNA, seems to be a major player in regulating such unusual organization. An important contribution to this uniqueness stems from the intrinsically disordered nature of this highly abundant chromosomal protein in neurons. Upon its binding to methylated/hydroxymethylated DNA, MeCP2 is able to recruit a plethora of interacting protein and RNA partners...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28439102/mecp2-regulated-mirnas-control-early-human-neurogenesis-through-differential-effects-on-erk-and-akt-signaling
#9
N Mellios, D A Feldman, S D Sheridan, J P K Ip, S Kwok, S K Amoah, B Rosen, B A Rodriguez, B Crawford, R Swaminathan, S Chou, Y Li, M Ziats, C Ernst, R Jaenisch, S J Haggarty, M Sur
Rett syndrome (RTT) is an X-linked, neurodevelopmental disorder caused primarily by mutations in the methyl-CpG-binding protein 2 (MECP2) gene, which encodes a multifunctional epigenetic regulator with known links to a wide spectrum of neuropsychiatric disorders. Although postnatal functions of MeCP2 have been thoroughly investigated, its role in prenatal brain development remains poorly understood. Given the well-established importance of microRNAs (miRNAs) in neurogenesis, we employed isogenic human RTT patient-derived induced pluripotent stem cell (iPSC) and MeCP2 short hairpin RNA knockdown approaches to identify novel MeCP2-regulated miRNAs enriched during early human neuronal development...
April 2018: Molecular Psychiatry
https://www.readbyqxmd.com/read/28395743/generation-of-a-clonal-induced-pluripotent-stem-cell-ipsc-line-expressing-the-mutant-mecp2-allele-from-a-rett-syndrome-patient-fibroblast-line
#10
Lisa Hunihan, Jeffrey Brown, Angela Cacace, Alda Fernandes, Andrea Weston
Human fibroblast cells collected from a 3-year old, female Rett Syndrome patient with a 32bp deletion in the X-linked MECP2 gene were obtained from the Coriell Institute. Fibroblasts were reprogrammed to iPSC cells using a Sendai-virus delivery system expressing human KOSM transcription factors. Cell-line pluripotency was demonstrated by gene expression, immunocytochemistry, in-vitro differentiation trilineage capacity and was of normal karyotype. Interestingly, subsequent clones retained the epigenetic memory of the parent fibroblasts allowing for the segregation of wild-type and mutant expressing clones...
April 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28270572/creb-signaling-is-involved-in-rett-syndrome-pathogenesis
#11
Qian Bu, Anxin Wang, Hamdi Hamzah, Alex Waldman, Keer Jiang, Qiping Dong, Ronghui Li, Jason Kim, Daniel Turner, Qiang Chang
Rett syndrome (RTT) is a debilitating neurodevelopmental disorder caused by mutations in the MECP2 gene. To facilitate the study of cellular mechanisms in human cells, we established several human stem cell lines: human embryonic stem cell (hESC) line carrying the common T158M mutation (MECP2T158M/T158M ), hESC line expressing no MECP2 (MECP2-KO), congenic pair of wild-type and mutant RTT patient-specific induced pluripotent stem cell (iPSC) line carrying the V247fs mutation (V247fs-WT and V247fs-MT), and iPSC line in which the V247fs mutation was corrected by CRISPR/Cas9-based genome editing (V247fs-MT-correction)...
March 29, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28139724/accumulated-quiescent-neural-stem-cells-in-adult-hippocampus-of-the-mouse-model-for-the-mecp2-duplication-syndrome
#12
Zhifang Chen, Xiao Li, Jingjing Zhou, Bo Yuan, Bin Yu, Dali Tong, Cheng Cheng, Yinqi Shao, Shengnan Xia, Ran Zhang, Jingwen Lyu, Xiuya Yu, Chen Dong, Wen-Hao Zhou, Zilong Qiu
Duplications of Methyl CpG binding protein 2 (MECP2) -containing segments lead to the MECP2 duplication syndrome, in which severe autistic symptoms were identified. Whether adult neurogenesis may play a role in pathogenesis of autism and the role of MECP2 on state determination of adult neural stem cells (NSCs) remain largely unclear. Using a MECP2 transgenic (TG) mouse model for the MECP2 duplication syndrome, we found that adult hippocampal quiescent NSCs were significantly accumulated in TG mice comparing to wild type (WT) mice, the neural progenitor cells (NPCs) were reduced and the neuroblasts were increased in adult hippocampi of MECP2 TG mice...
January 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28007906/igf1-neuronal-response-in-the-absence-of-mecp2-is-dependent-on-tralpha-3
#13
Janaina S de Souza, Cassiano Carromeu, Laila B Torres, Bruno H S Araujo, Fernanda R Cugola, Rui M B Maciel, Alysson R Muotri, Gisele Giannocco
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder in which the MECP2 (methyl CpG-binding protein 2) gene is mutated. Recent studies showed that RTT-derived neurons have many cellular deficits when compared to control, such as: less synapses, lower dendritic arborization and reduced spine density. Interestingly, treatment of RTT-derived neurons with Insulin-like Growth Factor 1 (IGF1) could rescue some of these cellular phenotypes. Given the critical role of IGF1 during neurodevelopment, the present study used human induced pluripotent stem cells (iPSCs) from RTT and control individuals to investigate the gene expression profile of IGF1 and IGF1R on different developmental stages of differentiation...
January 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/27732849/mecp2-is-post-transcriptionally-regulated-during-human-neurodevelopment-by-combinatorial-action-of-rna-binding-proteins-and-mirnas
#14
Deivid C Rodrigues, Dae-Sung Kim, Guang Yang, Kirill Zaslavsky, Kevin C H Ha, Rebecca S F Mok, P Joel Ross, Melody Zhao, Alina Piekna, Wei Wei, Benjamin J Blencowe, Quaid Morris, James Ellis
A progressive increase in MECP2 protein levels is a crucial and precisely regulated event during neurodevelopment, but the underlying mechanism is unclear. We report that MECP2 is regulated post-transcriptionally during in vitro differentiation of human embryonic stem cells (hESCs) into cortical neurons. Using reporters to identify functional RNA sequences in the MECP2 3' UTR and genetic manipulations to explore the role of interacting factors on endogenous MECP2, we discover combinatorial mechanisms that regulate RNA stability and translation...
October 11, 2016: Cell Reports
https://www.readbyqxmd.com/read/27379379/choline-ameliorates-disease-phenotypes-in-human-ipsc-models-of-rett-syndrome
#15
Eunice W M Chin, Guillaume Marcy, Su-In Yoon, Dongliang Ma, Francisco J Rosales, George J Augustine, Eyleen L K Goh
Rett syndrome (RTT) is a postnatal neurodevelopmental disorder that primarily affects girls. Mutations in the methyl-CpG-binding protein 2 (MECP2) gene account for approximately 95 % of all RTT cases. To model RTT in vitro, we generated induced pluripotent stem cells (iPSCs) from fibroblasts of two RTT patients with different mutations (MECP2 (R306C) and MECP2 (1155Δ32)) in their MECP2 gene. We found that these iPSCs were capable of differentiating into functional neurons. Compared to control neurons, the RTT iPSC-derived cells had reduced soma size and a decreased amount of synaptic input, evident both as fewer Synapsin 1-positive puncta and a lower frequency of spontaneous excitatory postsynaptic currents...
September 2016: Neuromolecular Medicine
https://www.readbyqxmd.com/read/27071793/modeling-rett-syndrome-using-human-induced-pluripotent-stem-cells
#16
REVIEW
Tomoko Andoh-Noda, Michiko O Inouye, Kunio Miyake, Takeo Kubota, Hideyuki Okano, Wado Akamatsu
Rett syndrome (RTT) is one of a group of neurodevelopmental disorders typically characterized by deficits in the X-linked gene MECP2 (methyl-CpG binding protein 2). The MECP2 gene encodes a multifunctional protein involved in transcriptional repression, transcriptional activation, chromatin remodeling, and RNA splicing. Genetic deletion of Mecp2 in mice revealed neuronal disabilities including RTT-like phenotypes and provided an excellent platform for understanding the pathogenesis of RTT. So far, there are no effective pharmacological treatments for RTT because the role of MECP2 in RTT is incompletely understood...
2016: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/27066911/a-mir-372-let-7-axis-regulates-human-germ-versus-somatic-cell-fates
#17
Nam D Tran, Michael Kissner, Deepa Subramanyam, Ronald J Parchem, Diana J Laird, Robert H Blelloch
The embryonic stem cell cycle (ESCC) and let-7 families of miRNAs function antagonistically in the switch between mouse embryonic stem cell self-renewal and somatic differentiation. Here, we report that the human ESCC miRNA miR-372 and let-7 act antagonistically in germline differentiation from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (iPSCs). hESC and iPSC-derived primordial germ cell-like cells (PGCLCs) expressed high levels of miR-372 and conversely, somatic cells expressed high levels of let-7...
July 2016: Stem Cells
https://www.readbyqxmd.com/read/27032601/proliferation-and-differentiation-deficits-are-a-major-convergence-point-for-neurodevelopmental-disorders
#18
REVIEW
Carl Ernst
Several lines of evidence suggest that proliferation and differentiation in neural stem cells (NSCs) are a major convergence point of neurodevelopmental disorders (NDDs). Most genes with truncating mutations are implicated in NSC proliferation and differentiation (e.g., MBD5, CDKL5, and MECP2). Similarly, reciprocal deletion/duplication copy-number variants (CNVs), such as 1q21.1 and 16p11.2, are inversely correlated with head size. In addition, pathways such as MAPK, mTOR, and RAS, which are important in cancer, a disease of uncontrolled cell proliferation, are implicated in NDDs...
May 2016: Trends in Neurosciences
https://www.readbyqxmd.com/read/26944080/layered-hydrogels-accelerate-ipsc-derived-neuronal-maturation-and-reveal-migration-defects-caused-by-mecp2-dysfunction
#19
Zhen-Ning Zhang, Beatriz C Freitas, Hao Qian, Jacques Lux, Allan Acab, Cleber A Trujillo, Roberto H Herai, Viet Anh Nguyen Huu, Jessica H Wen, Shivanjali Joshi-Barr, Jerome V Karpiak, Adam J Engler, Xiang-Dong Fu, Alysson R Muotri, Adah Almutairi
Probing a wide range of cellular phenotypes in neurodevelopmental disorders using patient-derived neural progenitor cells (NPCs) can be facilitated by 3D assays, as 2D systems cannot entirely recapitulate the arrangement of cells in the brain. Here, we developed a previously unidentified 3D migration and differentiation assay in layered hydrogels to examine how these processes are affected in neurodevelopmental disorders, such as Rett syndrome. Our soft 3D system mimics the brain environment and accelerates maturation of neurons from human induced pluripotent stem cell (iPSC)-derived NPCs, yielding electrophysiologically active neurons within just 3 wk...
March 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26733678/kcc2-rescues-functional-deficits-in-human-neurons-derived-from-patients-with-rett-syndrome
#20
Xin Tang, Julie Kim, Li Zhou, Eric Wengert, Lei Zhang, Zheng Wu, Cassiano Carromeu, Alysson R Muotri, Maria C N Marchetto, Fred H Gage, Gong Chen
Rett syndrome is a severe form of autism spectrum disorder, mainly caused by mutations of a single gene methyl CpG binding protein 2 (MeCP2) on the X chromosome. Patients with Rett syndrome exhibit a period of normal development followed by regression of brain function and the emergence of autistic behaviors. However, the mechanism behind the delayed onset of symptoms is largely unknown. Here we demonstrate that neuron-specific K(+)-Cl(-) cotransporter2 (KCC2) is a critical downstream gene target of MeCP2. We found that human neurons differentiated from induced pluripotent stem cells from patients with Rett syndrome showed a significant deficit in KCC2 expression and consequently a delayed GABA functional switch from excitation to inhibition...
January 19, 2016: Proceedings of the National Academy of Sciences of the United States of America
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