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Mecp2 stem cell

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https://www.readbyqxmd.com/read/28439102/mecp2-regulated-mirnas-control-early-human-neurogenesis-through-differential-effects-on-erk-and-akt-signaling
#1
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 25, 2017: 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
#2
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
#3
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 (MECP2(T158M/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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/26531500/epigenetic-regulation-of-mecp2-in-neural-stem-cells-and-adult-brain-implication-of-therapeutic-strategies-for-mecp2-related-neurodevelopmental-disorders
#13
Vichithra R B Liyanage, Robby M Zachariah, Mojgan Rastegar
No abstract text is available yet for this article.
December 2015: International Journal of Developmental Neuroscience
https://www.readbyqxmd.com/read/26456390/disruption-of-mecp2-attenuates-circadian-rhythm-in-crispr-cas9-based-rett-syndrome-model-mouse
#14
Yoshiki Tsuchiya, Yoichi Minami, Yasuhiro Umemura, Hitomi Watanabe, Daisuke Ono, Wataru Nakamura, Tomoyuki Takahashi, Sato Honma, Gen Kondoh, Toyojiro Matsuishi, Kazuhiro Yagita
Methyl-CpG-binding protein 2 (Mecp2) is an X-linked gene encoding a methylated DNA-binding nuclear protein which regulates transcriptional activity. The mutation of MECP2 in humans is associated with Rett syndrome (RTT), a neurodevelopmental disorder. Patients with RTT frequently show abnormal sleep patterns and sleep-associated problems, in addition to autistic symptoms, raising the possibility of circadian clock dysfunction in RTT. In this study, we investigated circadian clock function in Mecp2-deficient mice...
December 2015: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/26347316/altered-neuronal-network-and-rescue-in-a-human-mecp2-duplication-model
#15
COMPARATIVE STUDY
S Nageshappa, C Carromeu, C A Trujillo, P Mesci, I Espuny-Camacho, E Pasciuto, P Vanderhaeghen, C M Verfaillie, S Raitano, A Kumar, C M B Carvalho, C Bagni, M B Ramocki, B H S Araujo, L B Torres, J R Lupski, H Van Esch, A R Muotri
Increased dosage of methyl-CpG-binding protein-2 (MeCP2) results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSCs) from patients with the MECP2 duplication syndrome (MECP2dup), carrying different duplication sizes, to study the impact of increased MeCP2 dosage in human neurons. We show that cortical neurons derived from these different MECP2dup iPSC lines have increased synaptogenesis and dendritic complexity. In addition, using multi-electrodes arrays, we show that neuronal network synchronization was altered in MECP2dup-derived neurons...
February 2016: Molecular Psychiatry
https://www.readbyqxmd.com/read/26194112/investigation-of-genes-important-in-neurodevelopment-disorders-in-adult-human-brain
#16
Gilles Maussion, Alpha B Diallo, Carolina O Gigek, Elizabeth S Chen, Liam Crapper, Jean-Francois Théroux, Gary G Chen, Cristina Vasuta, Carl Ernst
Several neurodevelopmental disorders (NDDs) are caused by mutations in genes expressed in fetal brain, but little is known about these same genes in adult human brain. Here, we test the hypothesis that genes associated with NDDs continue to have a role in adult human brain to explore the idea that NDD symptoms may be partially a result of their adult function rather than just their neurodevelopmental function. To demonstrate adult brain function, we performed expression analyses and ChIPseq in human neural stem cell(NSC) lines at different developmental stages and adult human brain, targeting two genes associated with NDDs, SATB2 and EHMT1, and the WNT signaling gene TCF7L2, which has not been associated with NDDs...
October 2015: Human Genetics
https://www.readbyqxmd.com/read/26012557/differentiation-of-multipotent-neural-stem-cells-derived-from-rett-syndrome-patients-is-biased-toward-the-astrocytic-lineage
#17
Tomoko Andoh-Noda, Wado Akamatsu, Kunio Miyake, Takuya Matsumoto, Ryo Yamaguchi, Tsukasa Sanosaka, Yohei Okada, Tetsuro Kobayashi, Manabu Ohyama, Kinichi Nakashima, Hiroshi Kurosawa, Takeo Kubota, Hideyuki Okano
BACKGROUND: Rett syndrome (RTT) is one of the most prevalent neurodevelopmental disorders in females, caused by de novo mutations in the X-linked methyl CpG-binding protein 2 gene, MECP2. Although abnormal regulation of neuronal genes due to mutant MeCP2 is thought to induce autistic behavior and impaired development in RTT patients, precise cellular mechanisms underlying the aberrant neural progression remain unclear. RESULTS: Two sets of isogenic pairs of either wild-type or mutant MECP2-expressing human induced pluripotent stem cell (hiPSC) lines were generated from a single pair of 10-year-old RTT-monozygotic (MZ) female twins...
2015: Molecular Brain
https://www.readbyqxmd.com/read/26001598/effect-of-primary-culture-medium-type-for-culture-of-canine-fibroblasts-on-production-of-cloned-dogs
#18
Geon A Kim, Hyun Ju Oh, Min Jung Kim, Young Kwang Jo, Jin Choi, Jin Wook Kim, Tae Hee Lee, Byeong Chun Lee
Fibroblasts are common source of donor cells for SCNT. It is suggested that donor cells' microenvironment, including the primary culture, affects development of reconstructed embryos. To prove this, canine embryos were cloned with fibroblasts that were cultured in two different primary media (RCMEp vs. Dulbecco's modified Eagle's medium [DMEM]) and in vivo developments were compared with relative amount of stemness, reprogramming, apoptosis gene transcripts, and telomerase activity. Donor cells cultured in RCMEp contained a significantly higher amount of SOX2, NANOG, DPPA2, REXO1, HDAC, DNMT1, MECP2 and telomerase activity than those cultured in DMEM (P < 0...
September 1, 2015: Theriogenology
https://www.readbyqxmd.com/read/25722434/microrna-22-regulates-smooth-muscle-cell-differentiation-from-stem-cells-by-targeting-methyl-cpg-binding-protein-2
#19
Hanqing Zhao, Guanmei Wen, Guammei Wen, Yuan Huang, Xiaotian Yu, Qishan Chen, Tayyab Adeel Afzal, Le Anh Luong, Jianhua Zhu, Shu Ye, Ye Shu, Li Zhang, Qingzhong Xiao
OBJECTIVE: In this study, we attempted to uncover the functional impact of microRNA-22 (miR-22) and its target gene in smooth muscle cell (SMC) differentiation and delineate the molecular mechanism involved. APPROACH AND RESULTS: miR-22 was found to be significantly upregulated during SMC differentiation from embryonic stem cells and adventitia stem/progenitor cells. Enforced expression of miR-22 by its mimic, while knockdown of miR-22 by its antagomiR, promotes or inhibits SMC differentiation from embryonic stem cells and adventitia stem/progenitor cells, respectively...
April 2015: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/25644311/mecp2e1-isoform-mutation-affects-the-form-and-function-of-neurons-derived-from-rett-syndrome-patient-ips-cells
#20
Ugljesa Djuric, Aaron Y L Cheung, Wenbo Zhang, Rebecca S Mok, Wesley Lai, Alina Piekna, Jason A Hendry, P Joel Ross, Peter Pasceri, Dae-Sung Kim, Michael W Salter, James Ellis
MECP2 mutations cause the X-linked neurodevelopmental disorder Rett Syndrome (RTT) by consistently altering the protein encoded by the MECP2e1 alternative transcript. While mutations that simultaneously affect both MECP2e1 and MECP2e2 isoforms have been widely studied, the consequence of MECP2e1 deficiency on human neurons remains unknown. Here we report the first isoform-specific patient induced pluripotent stem cell (iPSC) model of RTT. RTTe1 patient iPS cell-derived neurons retain an inactive X-chromosome and express only the mutant allele...
April 2015: Neurobiology of Disease
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