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Mecp2 stem cell

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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Vichithra Rasangi Batuwita Liyanage, Robby Mathew Zachariah, James Ronald Davie, Mojgan Rastegar
Methyl CpG Binding Protein 2 (MeCP2) is an important epigenetic factor in the brain. MeCP2 expression is affected by different environmental insults including alcohol exposure. Accumulating evidence supports the role of aberrant MeCP2 expression in ethanol exposure-induced neurological symptoms. However, the underlying molecular mechanisms of ethanol-induced MeCP2 deregulation remain elusive. To study the effect of ethanol on Mecp2/MeCP2 expression during neurodifferentiation, we established an in vitro model of ethanol exposure, using differentiating embryonic brain-derived neural stem cells (NSC)...
March 2015: Experimental Neurology
Fang Liu, Jing-Jing Ni, Jun-Jie Huang, Zeng-Wei Kou, Feng-Yan Sun
PURPOSE: Astrocytes can be reactivated after cerebral ischemia by expressing nestin and other characteristic markers of neural stem cells (NSCs). However, the epigenetic features of reactive astrocytes are not well known. Methyl-CpG-binding protein 2 (MeCP2) is a vital transcriptional modulator in brain development. Although the expression and function of some phosphorylated MeCP2 isoforms have been clarified, phospho-serine 292 (pS292) MeCP2 has not yet drawn much attention. In this study, we used western blot analysis and immunohistochemical and immunofluorescent staining to reveal the expressive features of pS292 MeCP2 and MeCP2 in the adult rat striatum following transient middle cerebral artery occlusion (MCAO)...
March 2, 2015: Brain Research
K Griesi-Oliveira, A Acab, A R Gupta, D Y Sunaga, T Chailangkarn, X Nicol, Y Nunez, M F Walker, J D Murdoch, S J Sanders, T V Fernandez, W Ji, R P Lifton, E Vadasz, A Dietrich, D Pradhan, H Song, G-L Ming, X Gu, G Haddad, M C N Marchetto, N Spitzer, M R Passos-Bueno, M W State, A R Muotri
An increasing number of genetic variants have been implicated in autism spectrum disorders (ASDs), and the functional study of such variants will be critical for the elucidation of autism pathophysiology. Here, we report a de novo balanced translocation disruption of TRPC6, a cation channel, in a non-syndromic autistic individual. Using multiple models, such as dental pulp cells, induced pluripotent stem cell (iPSC)-derived neuronal cells and mouse models, we demonstrate that TRPC6 reduction or haploinsufficiency leads to altered neuronal development, morphology and function...
November 2015: Molecular Psychiatry
Max F Oginsky, Ningren Cui, Weiwei Zhong, Christopher M Johnson, Chun Jiang
Rett syndrome is an autism-spectrum disorder resulting from mutations to the X-linked gene, methyl-CpG binding protein 2 (MeCP2), which causes abnormalities in many systems. It is possible that the body may develop certain compensatory mechanisms to alleviate the abnormalities. The norepinephrine system originating mainly in the locus coeruleus (LC) is defective in Rett syndrome and Mecp2-null mice. LC neurons are subject to modulation by GABA, glutamate, and acetylcholine (ACh), providing an ideal system to test the compensatory hypothesis...
September 15, 2014: American Journal of Physiology. Cell Physiology
Gabriella Livide, Tommaso Patriarchi, Mariangela Amenduni, Sonia Amabile, Dag Yasui, Eleonora Calcagno, Caterina Lo Rizzo, Giulia De Falco, Cristina Ulivieri, Francesca Ariani, Francesca Mari, Maria Antonietta Mencarelli, Johannes Wilhelm Hell, Alessandra Renieri, Ilaria Meloni
Rett syndrome is a monogenic disease due to de novo mutations in either MECP2 or CDKL5 genes. In spite of their involvement in the same disease, a functional interaction between the two genes has not been proven. MeCP2 is a transcriptional regulator; CDKL5 encodes for a kinase protein that might be involved in the regulation of gene expression. Therefore, we hypothesized that mutations affecting the two genes may lead to similar phenotypes by dysregulating the expression of common genes. To test this hypothesis we used induced pluripotent stem (iPS) cells derived from fibroblasts of one Rett patient with a MECP2 mutation (p...
February 2015: European Journal of Human Genetics: EJHG
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