Application of reprogrammed patient cells to investigate the etiology of neurological and psychiatric disorders

doi:10.1007/s11515-012-1216-0

Front Biol

2012, Vol. 7

Issue (3) : 179-188 https://doi.org/10.1007/s11515-012-1216-0

REVIEW

Application of reprogrammed patient cells to investigate the etiology of neurological and psychiatric disorders

Kimberly M. CHRISTIAN^1,2(

), Hongjun SONG^1,2,3, Guo-li MING^1,2,3

1. Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; 2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; 3. The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

Download: PDF(234 KB) HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

Abstract

Cellular reprogramming allows for the de novo generation of human neurons and glial cells from patients with neurological and psychiatric disorders. Crucially, this technology preserves the genome of the donor individual and thus provides a unique opportunity for systematic investigation of genetic influences on neuronal pathophysiology. Although direct reprogramming of adult somatic cells to neurons is now possible, the majority of recent studies have used induced pluripotent stem cells (iPSCs) derived from patient fibroblasts to generate neural progenitors that can be differentiated to specific neural cell types. Investigations of monogenic diseases have established proof-of-principle for many aspects of cellular disease modeling, including targeted differentiation of neuronal populations and rescue of phenotypes in patient iPSC lines. Refinement of protocols to allow for efficient generation of iPSC lines from large patient cohorts may reveal common functional pathology and genetic interactions in diseases with a polygenic basis. We review several recent studies that illustrate the utility of iPSC-based cellular models of neurodevelopmental and neurodegenerative disorders to identify novel phenotypes and therapeutic approaches.

Keywords reprogramming iPSCs neurodevelopment neurodegeneration

Corresponding Author(s): CHRISTIAN Kimberly M.,Email:kchris12@jhmi.edu

Issue Date: 01 June 2012

Cite this article:

Hongjun SONG,Guo-li MING,Kimberly M. CHRISTIAN. Application of reprogrammed patient cells to investigate the etiology of neurological and psychiatric disorders[J]. Front Biol, 2012, 7(3): 179-188.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-012-1216-0
https://academic.hep.com.cn/fib/EN/Y2012/V7/I3/179

Fig.1 Simplified schematic diagram showing the development of cell-based assays for the investigation of neurological disease mechanisms.
(Blue-shaded box) Using fibroblasts obtained from patients and disease-free control subjects, human neurons can be generated through direct conversion or following an intervening stage of pluripotency. Disease-relevant neuronal populations can be enriched during the differentiation process through targeted protocols. (Pink-shaded box) Phenotypic analysis of human neurons generated from patients and control subjects may include any cell-based morphological or functional assay (e.g. dendritic development, synaptogenesis, synaptic connectivity, electrophysiology, intracellular signaling) as well as genetic and epigenetic profiling to produce complete transcriptomes and methylomes of homogenous populations. High-throughput approaches are particularly desirable for polygenic diseases to identify common functional disruptions across a heterogeneous patient population. (Yellow shaded box) Based on information acquired during the phenotypic screens or from previous investigations, targeted genetic manipulation can repair known mutations, which can then be subjected to phenotypic screens or introduced to neural progenitor populations to track development following genetic repair. Bioactive compounds can be similarly screened at various timepoints to evaluate potential to reverse or prevent phenotypic abnormalities. (Green-shaded box) Transplantation of patient-derived neural progenitors to mice can provide critical information regarding development and degeneration. Ultimately, cell-based screening and repair of neuronal dysfunction can be used to develop novel therapeutics for the patient population.

Disease	Mutation	Differentiation	Phenotype	Rescue	References
RTT	MeCP2missense, nonsense and frameshift mutations	GABAergic and glutamatergic neurons	Reduced soma size, number of spines, glutamatergic synapses; altered Ca²⁺ transients, sEPSCs, sIPSCs	IGF1 - partial increase in synapse number; Gentamycin - restored MeCP2 expression in nonsense mutation	Marchetto et al., 2010
TS	CACNA1C point mutation	Layer-specific cortical neurons	Differential gene expression; TH expression	~	Pa?ca et al., 2011
FD	IKBKAP point mutation	CNS and PNS precursors	IKBKAP splicing, neurogenesis, migration of neural crest precursors	Kinetin rescue of splicing and autonomic neuron differentiation	Lee et al., 2009
SZ	4bp deletion in DISC1- frameshift mutation	~	~	~	Chiang et al, 2011
SZ	Not known	Glutamatergic, GABAergic and dopaminergic neurons	Decreased neuronal connectivity, increased NRG1 expression	Loxapine rescue of neuronal connectivity deficits, NRG1 expression	Brennand et al., 2011
PD	LRRK2dominant missense mutation	Midbrain dopaminergic neurons	Differential gene expression; increased α-synuclein expression, increased susceptibility to H₂O_2, 6-OHDA, and MG-132	~	Nguyen et al., 2011
PD	PINK1 nonsense or missense mutations	Dopaminergic neurons	Impaired stress-induced translocation of Parkin to mitochondria; increased PGC-1α and mtDNA following depolarization	Overexpression of WT PINK1 restored translocation capacity and prevented PGC-1α increase	Seibler et al., 2011
PD	PARKINexon deletion(3 and/or 5)	Midbrain dopaminergic neurons	Increased spontaneous dopamine release; enhanced transcription of MAO-A, MAO-B; increased oxidative stress	Overexpression of WT-parkin rescued all phenotypes	Jiang et al., 2012
PD	α synuclein point mutation	Dopaminergic neurons	~	ZFN gene-editing; repair of point mutation in patient iPSCs; introduction of point mutation in hESCs	Soldner et al., 2011
AD	APP duplication in 2 patients (APP^Dp);No identified mutations in 2 sporadic AD patients (sAD)	Glutamatergic, GABAergic and cholinergic neurons	Increased amyloid-β, p-tau, and aGSK-3β expression in both APP^Dp lines and 1 of 2 sAD lines	Partial rescue of amyloid-β, p-tau, and aGSK-3β expression with γ and β-secretase inhibitors	Israel et al., 2012

Tab.1 Representative patient-specific iPSC studies of neurological disorders

1	Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S, Lipton S A, Ding S (2011). Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell , 9(2): 113-118 doi: 10.1016/j.stem.2011.07.002 pmid:21802386
2	Amir R E, Van den Veyver I B, Wan M, Tran C Q, Francke U, Zoghbi H Y (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet , 23(2): 185-188 doi: 10.1038/13810 pmid:10508514
3	Anderson S L, Qiu J, Rubin B Y (2003a). EGCG corrects aberrant splicing of IKAP mRNA in cells from patients with familial dysautonomia. Biochem Biophys Res Commun , 310(2): 627-633 doi: 10.1016/j.bbrc.2003.09.019 pmid:14521957
4	Anderson S L, Qiu J, Rubin B Y (2003b). Tocotrienols induce IKBKAP expression: a possible therapy for familial dysautonomia. Biochem Biophys Res Commun , 306(1): 303-309 doi: 10.1016/S0006-291X(03)00971-9 pmid:12788105
5	Bock C, Kiskinis E, Verstappen G, Gu H, Boulting G, Smith Z D, Ziller M, Croft G F, Amoroso M W, Oakley D H, Gnirke A, Eggan K, Meissner A (2011). Reference Maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell , 144(3): 439-452 doi: 10.1016/j.cell.2010.12.032 pmid:21295703
6	Boulting G L, Kiskinis E, Croft G F, Amoroso M W, Oakley D H, Wainger B J, Williams D J, Kahler D J, Yamaki M, Davidow L, Rodolfa C T, Dimos J T, Mikkilineni S, MacDermott A B, Woolf C J, Henderson C E, Wichterle H, Eggan K (2011). A functionally characterized test set of human induced pluripotent stem cells. Nat Biotechnol , 29(3): 279-286 doi: 10.1038/nbt.1783 pmid:21293464
7	Brennand K J, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, Li Y, Mu Y, Chen G, Yu D, McCarthy S, Sebat J, Gage F H (2011). Modelling schizophrenia using human induced pluripotent stem cells. Nature , 473(7346): 221-225 doi: 10.1038/nature09915 pmid:21490598
8	Caiazzo M, Dell’Anno M T, Dvoretskova E, Lazarevic D, Taverna S, Leo D, Sotnikova T D, Menegon A, Roncaglia P, Colciago G, Russo G, Carninci P, Pezzoli G, Gainetdinov R R, Gustincich S, Dityatev A, Broccoli V (2011). Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature , 476(7359): 224-227 doi: 10.1038/nature10284 pmid:21725324
9	Chambers S M, Studer L (2011). Cell fate plug and play: direct reprogramming and induced pluripotency. Cell , 145(6): 827-830 doi: 10.1016/j.cell.2011.05.036 pmid:21663788
10	Cheung A Y, Horvath L M, Grafodatskaya D, Pasceri P, Weksberg R, Hotta A, Carrel L, Ellis J (2011). Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation. Hum Mol Genet , 20(11): 2103-2115 doi: 10.1093/hmg/ddr093 pmid:21372149
11	Chiang C H, Su Y, Wen Z, Yoritomo N, Ross C A, Margolis R L, Song H, Ming G L (2011). Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation. Mol Psychiatry , 16(4): 358-360 doi: 10.1038/mp.2011.13 pmid:21339753
12	Duan X, Chang J H, Ge S, Faulkner R L, Kim J Y, Kitabatake Y, Liu X B, Yang C H, Jordan J D, Ma D K, Liu C Y, Ganesan S, Cheng H J, Ming G L, Lu B, Song H (2007). Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell , 130(6): 1146-1158 doi: 10.1016/j.cell.2007.07.010 pmid:17825401
13	Falk A, Koch P, Kesavan J, Takashima Y, Ladewig J, Alexander M, Wiskow O, Tailor J, Trotter M, Pollard S, Smith A, Brüstle O (2012). Capture of neuroepithelial-like stem cells from pluripotent stem cells provides a versatile system for in vitro production of human neurons. PLoS ONE , 7(1): e29597 doi: 10.1371/journal.pone.0029597 pmid:22272239
14	Faulkner R L, Jang M H, Liu X B, Duan X, Sailor K A, Kim J Y, Ge S, Jones E G, Ming G L, Song H, Cheng H J (2008). Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain. Proc Natl Acad Sci USA , 105(37): 14157-14162 doi: 10.1073/pnas.0806658105 pmid:18780780
15	Gore A, Li Z, Fung H L, Young J E, Agarwal S, Antosiewicz-Bourget J, Canto I, Giorgetti A, Israel M A, Kiskinis E, Lee J H, Loh Y H, Manos P D, Montserrat N, Panopoulos A D, Ruiz S, Wilbert M L, Yu J, Kirkness E F, Izpisua Belmonte J C, Rossi D J, Thomson J A, Eggan K, Daley G Q, Goldstein L S, Zhang K (2011). Somatic coding mutations in human induced pluripotent stem cells. Nature , 471(7336): 63-67 doi: 10.1038/nature09805 pmid:21368825
16	Hansen D V, Rubenstein J L, Kriegstein A R (2011). Deriving excitatory neurons of the neocortex from pluripotent stem cells. Neuron , 70(4): 645-660 doi: 10.1016/j.neuron.2011.05.006 pmid:21609822
17	Harrison P J, Weinberger D R (2005). Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry , 10:40-68
18	Herbert M R (2010). Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Curr Opin Neurol , 23(2): 103-110
19	Hussein S M, Batada N N, Vuoristo S, Ching R W, Autio R, N?rv? E, Ng S, Sourour M, H?m?l?inen R, Olsson C, Lundin K, Mikkola M, Trokovic R, Peitz M, Brüstle O, Bazett-Jones D P, Alitalo K, Lahesmaa R, Nagy A, Otonkoski T (2011). Copy number variation and selection during reprogramming to pluripotency. Nature , 471(7336): 58-62 doi: 10.1038/nature09871 pmid:21368824
20	Israel M A, Yuan S H, Bardy C, Reyna S M, Mu Y, Herrera C, Hefferan M P, Van Gorp S, Nazor K L, Boscolo F S, Carson C T, Laurent L C, Marsala M, Gage F H, Remes A M, Koo E H, Goldstein L S (2012). Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature , 482(7384): 216-220 pmid:22278060
21	Jiang H, Ren Y, Yuen E Y, Zhong P, Ghaedi M, Hu Z, Azabdaftari G, Nakaso K, Yan Z, Feng J (2012). Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells. Nat Commun , 3: 668 doi: 10.1038/ncomms1669 pmid:22314364
22	Juopperi T A, Song H, Ming G L (2011). Modeling neurological diseases using patient-derived induced pluripotent stem cells. Future Neurol , 6(3): 363-373 doi: 10.2217/fnl.11.14 pmid:21731471
23	Keller F, Persico A M (2003). The neurobiological context of autism. Mol Neurobiol 28(1): 1-22
24	Kim J Y, Duan X, Liu C Y, Jang M H, Guo J U, Pow-anpongkul N, Kang E, Song H, Ming G L (2009). DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron , 63(6): 761-773 doi: 10.1016/j.neuron.2009.08.008 pmid:19778506
25	Kim K Y, Hysolli E, Park I H (2011). Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome. Proc Natl Acad Sci USA , 108(34): 14169-14174 doi: 10.1073/pnas.1018979108 pmid:21807996
26	Koch P, Opitz T, Steinbeck J A, Ladewig J, Brüstle O (2009). A rosette-type, self-renewing human ES cell-derived neural stem cell with potential for in vitro instruction and synaptic integration. Proc Natl Acad Sci USA , 106(9): 3225-3230 doi: 10.1073/pnas.0808387106 pmid:19218428
27	Krencik R, Weick J P, Liu Y, Zhang Z J, Zhang S C (2011). Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nat Biotechnol , 29(6): 528-534 doi: 10.1038/nbt.1877 pmid:21602806
28	Lee G, Papapetrou E P, Kim H, Chambers S M, Tomishima M J, Fasano C A, Ganat Y M, Menon J, Shimizu F, Viale A, Tabar V, Sadelain M, Studer L (2009). Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature , 461(7262): 402-406 doi: 10.1038/nature08320 pmid:19693009
29	Lister R, Pelizzola M, Kida Y S, Hawkins R D, Nery J R, Hon G, Antosiewicz-Bourget J, O’Malley R, Castanon R, Klugman S, Downes M, Yu R, Stewart R, Ren B, Thomson J A, Evans R M, Ecker J R (2011). Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature , 471(7336): 68-73 doi: 10.1038/nature09798 pmid:21289626
30	Mao Y, Ge X, Frank C L, Madison J M, Koehler A N, Doud M K, Tassa C, Berry E M, Soda T, Singh K K, Biechele T, Petryshen T L, Moon R T, Haggarty S J, Tsai L H (2009). Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell , 136(6): 1017-1031 doi: 10.1016/j.cell.2008.12.044 pmid:19303846
31	Martin I, Dawson V L, Dawson T M (2011). Recent advances in the genetics of Parkinson’s disease. Annu Rev Genomics Hum Genet , 12(1): 301-325 doi: 10.1146/annurev-genom-082410-101440 pmid:21639795
32	Marchetto M C, Carromeu C, Acab A, Yu D, Yeo G W, Mu Y, Chen G, Gage F H, Muotri A R (2010). A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell , 143(4): 527-39
33	Millar J K, Wilson-Annan J C, Anderson S, Christie S, Taylor M S, Semple C A, Devon R S, St Clair D M, Muir W J, Blackwood D H, Porteous D J (2000). Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet , 9(9): 1415-1423 doi: 10.1093/hmg/9.9.1415 pmid:10814723
34	Nguyen H N, Byers B, Cord B, Shcheglovitov A, Byrne J, Gujar P, Kee K, Schüle B, Dolmetsch R E, Langston W, Palmer T D, Pera R R (2011). LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell , 8(3): 267-280 doi: 10.1016/j.stem.2011.01.013 pmid:21362567
35	Pang Z P, Yang N, Vierbuchen T, Ostermeier A, Fuentes D R, Yang T Q, Citri A, Sebastiano V, Marro S, Südhof T C, Wernig M (2011). Induction of human neuronal cells by defined transcription factors. Nature , 476(7359): 220-223 pmid:21617644
36	Park I H, Zhao R, West J A, Yabuuchi A, Huo H, Ince T A, Lerou P H, Lensch M W, Daley G Q (2008). Reprogramming of human somatic cells to pluripotency with defined factors. Nature , 451(7175): 141-146 doi: 10.1038/nature06534 pmid:18157115
37	Pa?ca S P, Portmann T, Voineagu I, Yazawa M, Shcheglovitov A, Pa?ca A M, Cord B, Palmer T D, Chikahisa S, Nishino S, Bernstein J A, Hallmayer J, Geschwind D H, Dolmetsch R E (2011). Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med , 17(12): 1657-1662 doi: 10.1038/nm.2576 pmid:22120178
38	Pfisterer U, Kirkeby A, Torper O, Wood J, Nelander J, Dufour A, Bj?rklund A, Lindvall O, Jakobsson J, Parmar M (2011). Direct conversion of human fibroblasts to dopaminergic neurons. Proc Natl Acad Sci USA , 108(25): 10343-10348 doi: 10.1073/pnas.1105135108 pmid:21646515
39	Pomp O, Dreesen O, Leong D F, Meller-Pomp O, Tan T T, Zhou F, Colman A (2011). Unexpected X chromosome skewing during culture and reprogramming of human somatic cells can be alleviated by exogenous telomerase. Cell Stem Cell , 9(2): 156-165 doi: 10.1016/j.stem.2011.06.004 pmid:21816366
40	Qiang L, Fujita R, Yamashita T, Angulo S, Rhinn H, Rhee D, Doege C, Chau L, Aubry L, Vanti W B, Moreno H, Abeliovich A (2011). Directed conversion of Alzheimer’s disease patient skin fibroblasts into functional neurons. Cell , 146(3): 359-371 doi: 10.1016/j.cell.2011.07.007 pmid:21816272
41	Ross C A, Margolis R L, Reading S A, Pletnikov M, Coyle J T (2006). Neurobiology of schizophrenia. Neuron , 52(1): 139-153 doi: 10.1016/j.neuron.2006.09.015 pmid:17015232
42	Sachs N A, Sawa A, Holmes S E, Ross C A, DeLisi L E, Margolis R L (2005). A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder. Mol Psychiatry , 10(8): 758-764 doi: 10.1038/sj.mp.4001667 pmid:15940305
43	Seibler P, Graziotto J, Jeong H, Simunovic F, Klein C, Krainc D (2011). Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells. J Neurosci , 31(16): 5970-5976 doi: 10.1523/JNEUROSCI.4441-10.2011 pmid:21508222
44	Shi Y, Kirwan P, Smith J, Robinson H P, Livesey F J (2012). Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat Neurosci , 15(3): 477-486 doi: 10.1038/nn.3041 pmid:22306606
45	Slaugenhaupt S A, Blumenfeld A, Gill S P, Leyne M, Mull J, Cuajungco M P, Liebert C B, Chadwick B, Idelson M, Reznik L, Robbins C, Makalowska I, Brownstein M, Krappmann D, Scheidereit C, Maayan C, Axelrod F B, Gusella J F (2001). Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet , 68(3): 598-605 doi: 10.1086/318810 pmid:11179008
46	Slaugenhaupt S A, Mull J, Leyne M, Cuajungco M P, Gill S P, Hims M M, Quintero F, Axelrod F B, Gusella J F (2003). Rescue of a human mRNA splicing defect by the plant cytokinin kinetin. Hum Mol Genet , 13(4): 429-436 doi: 10.1093/hmg/ddh046 pmid:14709595
47	Soldner F, Laganière J, Cheng A W, Hockemeyer D, Gao Q, Alagappan R, Khurana V, Golbe L I, Myers R H, Lindquist S, Zhang L, Guschin D, Fong L K, Vu B J, Meng X, Urnov F D, Rebar E J, Gregory P D, Zhang H S, Jaenisch R (2011). Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell , 146(2): 318-331 doi: 10.1016/j.cell.2011.06.019 pmid:21757228
48	Spitzer N C (2006). Electrical activity in early neuronal development. Nature , 444(7120): 707-712 doi: 10.1038/nature05300 pmid:17151658
49	St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G, Gosden C, Evans H J (1990). Association within a family of a balanced autosomal translocation with major mental illness. Lancet , 336(8706): 13-16 doi: 10.1016/0140-6736(90)91520-K pmid:1973210
50	Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell , 131(5): 861-872 doi: 10.1016/j.cell.2007.11.019 pmid:18035408
51	Takahashi K, Yamanaka S (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell , 126(4): 663-676 doi: 10.1016/j.cell.2006.07.024 pmid:16904174
52	Tchieu J, Kuoy E, Chin M H, Trinh H, Patterson M, Sherman S P, Aimiuwu O, Lindgren A, Hakimian S, Zack J A, Clark A T, Pyle A D, Lowry W E, Plath K (2010). Female human iPSCs retain an inactive X chromosome. Cell Stem Cell , 7(3): 329-342 doi: 10.1016/j.stem.2010.06.024 pmid:20727844
53	Tropea D, Giacometti E, Wilson N R, Beard C, McCurry C, Fu D D, Flannery R, Jaenisch R, Sur M (2009). Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci USA , 106(6): 2029-2034 doi: 10.1073/pnas.0812394106 pmid:19208815
54	Uhlhaas P J, Singer W (2010). Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci , 11(2): 100-113 doi: 10.1038/nrn2774 pmid:20087360
55	Vierbuchen T, Ostermeier A, Pang Z P, Kokubu Y, Südhof T C, Wernig M (2010). Direct conversion of fibroblasts to functional neurons by defined factors. Nature , 463(7284): 1035-1041 doi: 10.1038/nature08797 pmid:20107439
56	Weinberger D R (1987). Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry , 44(7): 660-669 doi: 10.1001/archpsyc.1987.01800190080012 pmid:3606332
57	Yoo A S, Sun A X, Li L, Shcheglovitov A, Portmann T, Li Y, Lee-Messer C, Dolmetsch R E, Tsien R W, Crabtree G R (2011). MicroRNA-mediated conversion of human fibroblasts to neurons. Nature , 476(7359): 228-231 doi: 10.1038/nature10323 pmid:21753754
58	Yu J, Vodyanik M A, SmugaOtto K, Antosiewicz-Bourget J, Frane J L, Tian S, Nie J, Jonsdottir G A, Ruotti V, Stewart R, Slukvin I I, Thomson J A (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science , 318(5858): 1917-1920 doi: 10.1126/science.1151526 pmid:18029452

[1]	Rachel Babij,Natalia De Marco Garcia. Neuronal activity controls the development of interneurons in the somatosensory cortex[J]. Front. Biol., 2016, 11(6): 459-470.
[2]	Behnam Ebrahimi. Chemical-only reprogramming to pluripotency[J]. Front. Biol., 2016, 11(2): 75-84.
[3]	Xin Xin Yu,Vimala Bondada,Colin Rogers,Carolyn A. Meyer,Chen Guang Yu. Targeting ERK1/2-calpain 1-NF-κB signal transduction in secondary tissue damage and astrogliosis after spinal cord injury[J]. Front. Biol., 2015, 10(5): 427-438.
[4]	Yicheng Ding,Linda Howard,Louise Gallagher,Sanbing Shen. Regulation and postsynaptic binding of neurexins – drug targets for neurodevelopmental and neuropsychiatric disorders[J]. Front. Biol., 2015, 10(3): 239-251.
[5]	Diana GUALLAR,Jianlong WANG. RNA-binding proteins in pluripotency, differentiation, and reprogramming[J]. Front. Biol., 2014, 9(5): 389-409.
[6]	Aaron MCGEE,Guohui LI,Zhongming LU,Shenfeng QIU. Convergent synaptic and circuit substrates underlying autism genetic risks[J]. Front. Biol., 2014, 9(2): 137-150.
[7]	Abiodun AJAYI, Xin YU, Anna-Lena STR?M. The role of NADPH oxidase (NOX) enzymes in neurodegenerative disease[J]. Front Biol, 2013, 8(2): 175-188.
[8]	Jeffrey P. CANTLE, Xiao-Hong LU, Xiaofeng GU, X. William YANG. Cellular and molecular mechanisms implicated in pathogenesis of selective neurodegeneration in Huntington’s disease[J]. Front Biol, 2012, 7(5): 459-476.
[9]	Chen Guang YU. Distinct roles for ERK1 and ERK2 in pathophysiology of CNS[J]. Front Biol, 2012, 7(3): 267-276.
[10]	Richard D. Smrt, Xinyu Zhao, . Epigenetic regulation of neuronal dendrite and dendritic spine development[J]. Front. Biol., 2010, 5(4): 304-323.
[11]	Wei LI, Qi ZHOU. Epigenetic reprogramming: roads to pluripotency[J]. Front. Biol., 2010, 5(1): 8-11.

Viewed

Full text

Abstract

Cited

Shared

Discussed