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Neuronal Maturation Defect in Induced Pluripotent Stem Cells from Patients with Rett Syndrome

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Neuronal Maturation Defect in Induced Pluripotent Stem Cells from Patients with Rett Syndrome Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome Kun-Yong Kim, Eriona Hysolli, and In-Hyun Park1 Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520 Edited* by Sherman M. Weissman, Yale University, New Haven, CT, and approved July 13, 2011 (received for review December 29, 2010) Rett syndrome (RTT) is one of the most prevalent female neuro- MeCP2 recapitulates the RTT symptoms of the whole-body KO developmental disorders that cause severe mental retardation. mouse, implicating an essential role for MeCP2 in neurons (11). Mutations in methyl CpG binding protein 2 (MeCP2) are mainly As neuronal stem cells differentiate into neurons, MeCP2 ex- responsible for RTT. Patients with classical RTT exhibit normal pression gradually increases. Recently, glial cells were also found – to express MeCP2 and to play an important role in pathogenesis development until age 6 18 mo, at which point they become – symptomatic and display loss of language and motor skills, pur- of RTT (12 14). Regardless of the essential information on RTT disease poseful hand movements, and normal head growth. Murine ge- obtained from murine models, the phenotypes of the MeCP2 netic models and postmortem human brains have been used to null KO mouse are not identical to the human phenotypes. study the disease and enable the molecular dissection of RTT. In Homozygous MeCP2 null female mice are born to term and this work, we applied a recently developed reprogramming ap- survive until 4 wk after birth, and heterozygous MeCP2 female proach to generate a novel in vitro human RTT model. Induced mice do not show obvious RTT phenotypes (10). In contrast, pluripotent stem cells (iPSCs) were derived from RTT fibroblasts only heterozygous human females develop RTT, and homo- by overexpressing the reprogramming factors OCT4, SOX2, KLF4, zygotes do not survive. These results suggest that human MeCP2 and MYC. Intriguingly, whereas some iPSCs maintained X chromo- has a role distinct from murine MeCP2. Likewise, whereas mu- some inactivation, in others the X chromosome was reactivated. rine and human MeCP2 are essential for neuronal maturation Thus, iPSCs were isolated that retained a single active X chromo- but not for neurogenesis, Xenopus MeCP2 is critical for neuro- some expressing either mutant or WT MeCP2, as well as iPSCs genesis (15). Thus, developing a human RTT model that more with reactivated X chromosomes expressing both mutant and closely recapitulates the human disease is essential for a true WT MeCP2. When these cells underwent neuronal differentiation, understanding of human RTT. the mutant monoallelic or biallelelic RTT-iPSCs displayed a defect Postmortem human brain tissue samples have provided in- in neuronal maturation consistent with RTT phenotypes. Our valuable insight into RTT (16). Abnormal neuronal develop- ment, RTT-specific gene expression including MeCP2, and reli- in vitro model of RTT is an important tool allowing the further able epigenetic markers have been identified using postmortem investigation of the pathophysiology of RTT and the development brains from patients with RTT. However, the difficulty in of the curative therapeutics. obtaining live human brain tissues and cells from either healthy donors or RTT patients necessitates the development of an ett syndrome (RTT) is one of the most common causes of alternative approach to directly study neurons from human Rmental retardation in females, with an incidence of 1 in patients with RTT. Human embryonic stem cells (hESCs) are 10,000–15,000 female births (1). Signs and symptoms of RTT ap- considered an important cellular resource for studying disease pear at 6–18 mo after birth and typically include severe mental in vitro because of their features of self-renewal and pluri- retardation, absence of speech, stereotypic hand movements, ep- potency, which allow differentiation of cells of all three germ ileptic seizures, encephalopathy, and respiratory dysfunction (1). layers. The recent successful generation of induced pluripotent Mutations in methyl CpG binding protein 2 (MeCP2) were iden- stem cells (iPSCs) from patients’ somatic cells by ectopically tified as the primary genetic cause of RTT by Amir et al. (2). expressing four transcription factors (Oct4, Sox2, Myc, and Klf4) BIOLOGY Characterization of MeCP2 has revealed three functional do- allows the derivation of pluripotent stem cells from patients with DEVELOPMENTAL mains: a methyl CpG binding domain (MBD), a transcriptional re- Mendelian genetic or nongenetic diseases. Because human pression domain (TRD), and a carboxyl terminal domain (CTD). iPSCs acquire similar features as hESCs and can differentiate The presence of the TRD in MeCP2 suggests a potential role of into cells of all three germ layers, including neuronal and glial MeCP2 in transcription repression, and indeed it is involved in cells, iPSCs provide an opportunity to study human neuronal gene silencing through binding to methylated CpG and chromatin disorders in vitro. iPSCs have been used to model human neu- ronal diseases, including spinal muscular atrophy, familial dys- remodeling (3). In addition, recent molecular and cellular studies – in mouse models and cell cultures have shown that MeCP2 also autonomia, and amyotrophic lateral sclerosis (17 19). iPSCs plays roles in transcription activation, long-range chromatin from patients with spinal muscular atrophy and familial dysau- remodeling, and regulation of alternative splicing (4, 5). tonomia exhibit the phenotypic characteristics of the respective diseases, whereas the in vitro phenotype of amyotrophic lateral More than 300 pathogenic mutations in MeCP2 have been fi described, most commonly missense or nonsense mutations and sclerosis is yet to be con rmed. most frequently located in the MBD, TRD, or CTD (6). MeCP2 Recently, the Muotri laboratory generated human iPSCs from is located on the X chromosome at Xq28. During normal de- patients with RTT using retroviral vector expressing the fore- velopment, one X chromosome in each cell randomly becomes going transcription factors (20). The female RTT-iPSCs thus generated exhibited the reactivation of randomly inactivated fi- inactivated, and females display a mosaicism of cells with either broblast X chromosome and expressed both WT and mutant paternal or maternal X chromosomes. In the case of RTT, var- iability in the inactivation of the WT or mutant MeCP2 leads to a spectrum of phenotypic severity (7–9). Indeed, females with RTT often exhibit nonrandom activation of X chromosomes Author contributions: K.-Y.K. and I.-H.P. designed research; K.-Y.K. and E.H. performed favoring the WT allele and resulting in subdued phenotypes (9). research; K.-Y.K., E.H., and I.-H.P. analyzed data; and K.-Y.K. and I.-H.P. wrote the paper. Mice with germline mutations in MeCP2 have provided key The authors declare no conflict of interest. models enabling the dissection of the developmental role of *This Direct Submission article had a prearranged editor. MeCP2 in RTT (10). These mice display several phenotypic 1To whom correspondence should be addressed. E-mail: [email protected]. characteristics mimicking human RTT. Although MeCP2 is This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. broadly expressed in most tissues, neuron-specific deletion of 1073/pnas.1018979108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1018979108 PNAS | August 23, 2011 | vol. 108 | no. 34 | 14169–14174 Downloaded by guest on September 30, 2021 MeCP2 from two active X chromosomes. When differentiated RTT1 RTT3 RTT2 RTT4 RTT5 A T158M E235fs Q244X R306C X487W into the neuronal lineage, RTT-iPSCs recapitulated the in vivo phenotypes, including synapse defects, smaller soma size, altered calcium signaling, and electrophysiological defects. That study 1 75 164 207 310 486 demonstrates the invaluable proof of principle of generating a human RTT syndrome model using iPSCs. In the present work, we similarly attempted to generate an B RTT1-iPS-13w RTT1-iPS-15m in vitro RTT model using human iPSCs. Expanding the work of the Muotri laboratory, we found that factor-based reprogram- ming produces both iPSCs that have the reactivated X chromo- somes and iPSCs that retain the randomly inactivated fibroblast X chromosome. which allows the generation of isogenic iPSC clones expressing either WT or mutant MeCP2. These two types of iPSC clones originate from the same fibroblasts and express the same genes except the genes in the X chromosome, including MeCP2. Thus, they are ideal isogenic cell lines for comparing the phenotypes caused by the given mutation. To examine the effect of MeCP2 mutations on neuronal differentiation, we applied monoallelic WT and mutant iPSCs, as well as biallelic iPSCs, to C D neuronal differentiation. The initial neuronal differentiation of mutant RTT iPSCs was not different from that of WT iPSCs and hESCs; however, during late neuronal maturation, the mutant RTT iPSCs exhibited defects mimicking the RTT syndrome phe- notypes. Along with providing an important tool for studying RTT RTT1-iPS-13w human disease, our results demonstrate the feasibility of gener- ating isogenic iPSCs to study X-linked monogenic disorders. to RTT1-Fibroblast Results Expression relative iPSCs from RTT Fibroblasts. As discussed earlier, MeCP2 has three RTT1-iPS-15m main domains: MBD, TRD, and CTD (Fig. 1A). Mutations in each of these domains or elsewhere, such as within the two nu- E Endoderm Mesoderm Ectoderm clear localization signals, lead to the improper regulation or lack of MeCP2 expression and are a primary cause of RTT. To in- vestigate the impact of mutations in each domain of MeCP2 on the manifestation of the in vitro RTT phenotype, we selected specific fibroblasts from patients with RTT with different muta- RTT1-iPS-13w tions to generate the following RTT-iPSCs for the domains of MeCP2: RTT1 (GM17880) for the MBD, RTT2 (GM16548) and RTT3 (GM07982) for the TRD and CTD, RTT4 (GM11270) for the TRD, and RTT5 (GM17567) for the CTD (Table 1).
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