Abstract
The inception of human-induced pluripotent stem cell (hiPSCs) technology has provided an exciting platform upon which the modelling and treatment of human neurodevelopmental and neuropsychiatric disorders may be expedited. Although the genetic architecture of these disorders is far more complex than previously imagined, many key loci have at last been identified. This has allowed in vivo and in vitro technologies to be refined to model specific high-penetrant genetic loci involved in both disorders. Animal models of neurodevelopmental disorders, such as schizophrenia and autism spectrum disorders, show limitations in recapitulating the full complexity and heterogeneity of human neurodevelopmental disease states. Indeed, patient-derived hiPSCs offer distinct advantages over classical animal models in the study of human neuropathologies. Here we have discussed the current, relative translational merit of hiPSCs in investigating human neurodevelopmental and neuropsychiatric disorders with a specific emphasis on the utility of such systems to aid in the identification of biomarkers. We have highlighted the promises and pitfalls of reprogramming cell fate for the study of these disorders and provide recommendations for future directions in this field in order to overcome current limitations. Ultimately, this will aid in the development of effective clinical strategies for diverse patient populations affected by these disorders with the aim of also leading to biomarker identification.
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References
Aasen T, Raya A, Barrero MJ, Garreta E, Consiglio A, Gonzalez F et al (2008) Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol 26(11):1276–1284. https://doi.org/10.1038/nbt.1503
Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23(2):185–188. https://doi.org/10.1038/13810
Anderson S, Vanderhaeghen P (2014) Cortical neurogenesis from pluripotent stem cells: complexity emerging from simplicity. Curr Opin Neurobiol 27:151–157. https://doi.org/10.1016/j.conb.2014.03.012
Ardhanareeswaran K, Mariani J, Coppola G, Abyzov A, Vaccarino FM (2017) Human induced pluripotent stem cells for modelling neurodevelopmental disorders. Nat Rev Neurol 13(5):265–278. https://doi.org/10.1038/nrneurol.2017.45
Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M (1995) Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 25(1):63–77
Bakkaloglu B, O'Roak BJ, Louvi A, Gupta AR, Abelson JF, Morgan TM et al (2008) Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am J Hum Genet 82(1):165–173. https://doi.org/10.1016/j.ajhg.2007.09.017
Bartolini G, Ciceri G, Marin O (2013) Integration of GABAergic interneurons into cortical cell assemblies: lessons from embryos and adults. Neuron 79(5):849–864. https://doi.org/10.1016/j.neuron.2013.08.014
Berkel S, Marshall CR, Weiss B, Howe J, Roeth R, Moog U et al (2010) Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Nat Genet 42(6):489–491. https://doi.org/10.1038/ng.589
Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69(3):89–95. https://doi.org/10.1067/mcp.2001.113989
Birey F, Andersen J, Makinson CD, Islam S, Wei W, Huber N et al (2017) Assembly of functionally integrated human forebrain spheroids. Nature 545(7652):54–59. https://doi.org/10.1038/nature22330
Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ (2001) Schizophrenia and affective disorders—cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet 69(2):428–433
Boksa P (2012) Abnormal synaptic pruning in schizophrenia: urban myth or reality? J Psychiatry Neurosci 37(2):75–77. https://doi.org/10.1503/jpn.120007
Bortone D, Polleux F (2009) KCC2 expression promotes the termination of cortical interneuron migration in a voltage-sensitive calcium-dependent manner. Neuron 62(1):53–71. https://doi.org/10.1016/j.neuron.2009.01.034
Boyle EA, Li YI, Pritchard JK (2017) An expanded view of complex traits: from polygenic to Omnigenic. Cell 169(7):1177–1186. https://doi.org/10.1016/j.cell.2017.05.038
Brandon NJ, Sawa A (2011) Linking neurodevelopmental and synaptic theories of mental illness through DISC1. Nat Rev Neurosci 12(12):707–722. https://doi.org/10.1038/nrn3120
Bravery CA (2015) Do human leukocyte antigen-typed cellular therapeutics based on induced pluripotent stem cells make commercial sense? Stem Cells Dev 24(1):1–10. https://doi.org/10.1089/scd.2014.0136
Brennand KJ, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S et al (2011) Modelling schizophrenia using human induced pluripotent stem cells. Nature 473(7346):221–225. https://doi.org/10.1038/nature09915
Bucan M, Abrahams BS, Wang K, Glessner JT, Herman EI, Sonnenblick LI et al (2009) Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet 5(6):e1000536. https://doi.org/10.1371/journal.pgen.1000536
Chaste P, Leboyer M (2012) Autism risk factors: genes, environment, and gene-environment interactions. Dialogues Clin Neurosci 14(3):281–292
Chen HM, DeLong CJ, Bame M, Rajapakse I, Herron TJ, McInnis MG, O’Shea KS (2014) Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients. Transl Psychiatry 4:e375. https://doi.org/10.1038/tp.2014.12
Chiang CH, Su Y, Wen Z, Yoritomo N, Ross CA, Margolis RL et al (2011) Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation. Mol Psychiatry 16(4):358–360. https://doi.org/10.1038/mp.2011.13
Chisholm K, Lin A, Abu-Akel A, Wood SJ (2015) The association between autism and schizophrenia spectrum disorders: a review of eight alternate models of co-occurrence. Neurosci Biobehav Rev 55:173–183. https://doi.org/10.1016/j.neubiorev.2015.04.012
Conrad DF, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y et al (2010) Origins and functional impact of copy number variation in the human genome. Nature 464(7289):704–712. https://doi.org/10.1038/nature08516
Crabtree GW, Sun Z, Kvajo M, Broek JA, Fenelon K, McKellar H et al (2017) Alteration of neuronal excitability and short-term synaptic plasticity in the prefrontal cortex of a mouse model of mental illness. J Neurosci 37(15):4158–4180. https://doi.org/10.1523/JNEUROSCI.4345-15.2017
Darville H, Poulet A, Rodet-Amsellem F, Chatrousse L, Pernelle J, Boissart C et al (2016) Human pluripotent stem cell-derived cortical neurons for high throughput medication screening in autism: a proof of concept study in SHANK3 Haploinsufficiency syndrome. EBioMedicine 9:293–305. https://doi.org/10.1016/j.ebiom.2016.05.032
Davidson S, Lear M, Shanley L, Hing B, Baizan-Edge A, Herwig A et al (2011) Differential activity by polymorphic variants of a remote enhancer that supports galanin expression in the hypothalamus and amygdala: implications for obesity, depression and alcoholism. Neuropsychopharmacology 36(11):2211–2221. https://doi.org/10.1038/npp.2011.93
Davis KL, Stewart DG, Friedman JI, Buchsbaum M, Harvey PD, Hof PR et al (2003) White matter changes in schizophrenia: evidence for myelin-related dysfunction. Arch Gen Psychiatry 60(5):443–456. https://doi.org/10.1001/archpsyc.60.5.443
Davis SW, Mortensen AH, Keisler JL, Zacharias AL, Gage PJ, Yamamura K, Camper SA (2016) beta-catenin is required in the neural crest and mesencephalon for pituitary gland organogenesis. BMC Dev Biol 16(1):16. https://doi.org/10.1186/s12861-016-0118-9
De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE et al (2014) Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515(7526):209–215. https://doi.org/10.1038/nature13772
Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y et al (2007) Disrupted-in-schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell 130(6):1146–1158. https://doi.org/10.1016/j.cell.2007.07.010
Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F et al (2007) Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 39(1):25–27. https://doi.org/10.1038/ng1933
Eiraku M, Sasai Y (2011) Mouse embryonic stem cell culture for generation of three-dimensional retinal and cortical tissues. Nat Protoc 7(1):69–79. https://doi.org/10.1038/nprot.2011.429
Eiraku M, Watanabe K, Matsuo-Takasaki M, Kawada M, Yonemura S, Matsumura M et al (2008) Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 3(5):519–532. https://doi.org/10.1016/j.stem.2008.09.002
Fernandez T, Morgan T, Davis N, Klin A, Morris A, Farhi A et al (2004) Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. Am J Hum Genet 74(6):1286–1293. https://doi.org/10.1086/421474
Fernandez T, Morgan T, Davis N, Klin A, Morris A, Farhi A et al (2008) Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. Am J Hum Genet 82(6):1385
Fietz SA, Kelava I, Vogt J, Wilsch-Brauninger M, Stenzel D, Fish JL et al (2010) OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling. Nat Neurosci 13(6):690–699. https://doi.org/10.1038/nn.2553
Fombonne E (2005) Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiatry 66(Suppl 10):3–8
Garber K (2015) RIKEN suspends first clinical trial involving induced pluripotent stem cells. Nat Biotechnol 33(9):890–891. https://doi.org/10.1038/nbt0915-890
Gauthier J, Spiegelman D, Piton A, Lafreniere RG, Laurent S, St-Onge J et al (2009) Novel de novo SHANK3 mutation in autistic patients. Am J Med Genet B Neuropsychiatr Genet 150B(3):421–424. https://doi.org/10.1002/ajmg.b.30822
Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S et al (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459(7246):569–573. https://doi.org/10.1038/nature07953
Gratten J, Visscher PM, Mowry BJ, Wray NR (2013) Interpreting the role of de novo protein-coding mutations in neuropsychiatric disease. Nat Genet 45(3):234–238. https://doi.org/10.1038/ng.2555
Guha S, Rees E, Darvasi A, Ivanov D, Ikeda M, Bergen SE et al (2013) Implication of a rare deletion at distal 16p11.2 in schizophrenia. JAMA Psychiatry 70(3):253–260. https://doi.org/10.1001/2013.jamapsychiatry.71
Hamlyn J, Duhig M, McGrath J, Scott J (2013) Modifiable risk factors for schizophrenia and autism–shared risk factors impacting on brain development. Neurobiol Dis 53:3–9. https://doi.org/10.1016/j.nbd.2012.10.023
Hannon E, Spiers H, Viana J, Pidsley R, Burrage J, Murphy TM et al (2016) Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci. Nat Neurosci 19(1):48–54. https://doi.org/10.1038/nn.4182
Hansen DV, Lui JH, Parker PR, Kriegstein AR (2010) Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature 464(7288):554–561. https://doi.org/10.1038/nature08845
Harrison PJ (2015) GABA circuitry, cells and molecular regulation in schizophrenia: life in the graveyard. Schizophr Res 167(1–3):108–110. https://doi.org/10.1016/j.schres.2015.02.003
Harrison PJ, Cader MZ, Geddes JR (2016) Reprogramming psychiatry: stem cells and bipolar disorder. Lancet 387(10021):823–825. https://doi.org/10.1016/S0140-6736(16)00235-X
Hawley RG (2008) Does retroviral insertional mutagenesis play a role in the generation of induced pluripotent stem cells? Mol Ther 16(8):1354–1355. https://doi.org/10.1038/mt.2008.142
Hing B, Davidson S, Lear M, Breen G, Quinn J, McGuffin P, MacKenzie A (2012) A polymorphism associated with depressive disorders differentially regulates brain derived neurotrophic factor promoter IV activity. Biol Psychiatry 71(7):618–626. https://doi.org/10.1016/j.biopsych.2011.11.030
Insel TR (2010) Rethinking schizophrenia. Nature 468(7321):187–193. https://doi.org/10.1038/nature09552
Jablensky A (2015) Schizophrenia or schizophrenias? The challenge of genetic parsing of a complex disorder. Am J Psychiatry 172(2):105–107. https://doi.org/10.1176/appi.ajp.2014.14111452
Jamain S, Quach H, Betancur C, Rastam M, Colineaux C, Gillberg IC et al (2003) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 34(1):27–29. https://doi.org/10.1038/ng1136
Kadoshima T, Sakaguchi H, Nakano T, Soen M, Ando S, Eiraku M, Sasai Y (2013) Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci U S A 110(50):20284–20289. https://doi.org/10.1073/pnas.1315710110
Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y et al (2005) A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol 7(12):1167–1178. https://doi.org/10.1038/ncb1328
Kapur S, Phillips AG, Insel TR (2012) Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it? Mol Psychiatry 17(12):1174–1179. https://doi.org/10.1038/mp.2012.105
Karzbrun E, Kshirsagar A, Cohen SR, Hanna JH, Reiner O (2018) Human brain organoids on a chip reveals the physics of folding. Nat Phys 14:515. https://doi.org/10.1038/s41567-018-0046-7
Kaufmann M, Schuffenhauer A, Fruh I, Klein J, Thiemeyer A, Rigo P et al (2015) High-throughput screening using iPSC-derived neuronal progenitors to identify compounds counteracting epigenetic gene silencing in fragile X syndrome. J Biomol Screen 20(9):1101–1111. https://doi.org/10.1177/1087057115588287
Kim HG, Kishikawa S, Higgins AW, Seong IS, Donovan DJ, Shen Y et al (2008) Disruption of neurexin 1 associated with autism spectrum disorder. Am J Hum Genet 82(1):199–207. https://doi.org/10.1016/j.ajhg.2007.09.011
Kirov G, Grozeva D, Norton N, Ivanov D, Mantripragada KK, Holmans P et al (2009) Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Hum Mol Genet 18(8):1497–1503. https://doi.org/10.1093/hmg/ddp043
Kobayashi K, Kuroda S, Fukata M, Nakamura T, Nagase T, Nomura N et al (1998) p140Sra-1 (specifically Rac1-associated protein) is a novel specific target for Rac1 small GTPase. J Biol Chem 273(1):291–295
Kubicki M, McCarley RW, Shenton ME (2005) Evidence for white matter abnormalities in schizophrenia. Curr Opin Psychiatry 18(2):121–134
Kumari D, Swaroop M, Southall N, Haung W, Zheng W, Usdin K (2015) High-throughput screening to identify compounds that increase fragile X mental retardation protein expression in neural stem cells differentiated from fragile X syndrome patient-derived induced pluripotent stem cells. Stem Cells Transl Med 4(7):800–808. https://doi.org/10.5966/sctm.2014-0278
Kunda P, Craig G, Dominguez V, Baum B (2003) Abi, Sra1, and Kette control the stability and localization of SCAR/WAVE to regulate the formation of actin-based protrusions. Curr Biol 13(21):1867–1875
Kuwahara A, Ozone C, Nakano T, Saito K, Eiraku M, Sasai Y (2015) Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue. Nat Commun 6:6286. https://doi.org/10.1038/ncomms7286
Lancaster MA (2018) Brain organoids get vascularized. Nat Biotechnol 36(5):407–408. https://doi.org/10.1038/nbt.4133
Lancaster MA, Knoblich JA (2014) Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc 9(10):2329–2340. https://doi.org/10.1038/nprot.2014.158
Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME et al (2013) Cerebral organoids model human brain development and microcephaly. Nature 501(7467):373–379. https://doi.org/10.1038/nature12517
Lancaster MA, Corsini NS, Burkland TR, Knoblich JA (2016) Guided self-organization recapitulates tissue architecture in a bioengineered brain organoid model. bioRxiv. https://doi.org/10.1101/049346
Laurent LC, Ulitsky I, Slavin I, Tran H, Schork A, Morey R et al (2011) Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 8(1):106–118. https://doi.org/10.1016/j.stem.2010.12.003
Lee MO, Moon SH, Jeong HC, Yi JY, Lee TH, Shim SH et al (2013) Inhibition of pluripotent stem cell-derived teratoma formation by small molecules. Proc Natl Acad Sci U S A 110(35):E3281–E3290. https://doi.org/10.1073/pnas.1303669110
Levy D, Ronemus M, Yamrom B, Lee YH, Leotta A, Kendall J et al (2011) Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70(5):886–897. https://doi.org/10.1016/j.neuron.2011.05.015
Li XJ, Du ZW, Zarnowska ED, Pankratz M, Hansen LO, Pearce RA, Zhang SC (2005) Specification of motoneurons from human embryonic stem cells. Nat Biotechnol 23(2):215–221. https://doi.org/10.1038/nbt1063
Li M, Zhao H, Ananiev GE, Musser MT, Ness KH, Maglaque DL et al (2017) Establishment of reporter lines for detecting fragile X mental retardation (FMR1) gene reactivation in human neural cells. Stem Cells 35(1):158–169. https://doi.org/10.1002/stem.2463
Lichtenstein P, Yip BH, Bjork C, Pawitan Y, Cannon TD, Sullivan PF, Hultman CM (2009) Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373(9659):234–239. https://doi.org/10.1016/S0140-6736(09)60072-6
Lipska BK, Peters T, Hyde TM, Halim N, Horowitz C, Mitkus S et al (2006) Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs. Hum Mol Genet 15(8):1245–1258. https://doi.org/10.1093/hmg/ddl040
Liu Y, Liu H, Sauvey C, Yao L, Zarnowska ED, Zhang SC (2013) Directed differentiation of forebrain GABA interneurons from human pluripotent stem cells. Nat Protoc 8(9):1670–1679. https://doi.org/10.1038/nprot.2013.106
Liu G, Rustom N, Litteljohn D, Bobyn J, Rudyk C, Anisman H, Hayley S (2014) Use of induced pluripotent stem cell derived neurons engineered to express BDNF for modulation of stressor related pathology. Front Cell Neurosci 8:316. https://doi.org/10.3389/fncel.2014.00316
Lu J, Zhong X, Liu H, Hao L, Huang CT, Sherafat MA et al (2016) Generation of serotonin neurons from human pluripotent stem cells. Nat Biotechnol 34(1):89–94. https://doi.org/10.1038/nbt.3435
MacQueen DA, Young JW, Cope ZA (2018) Cognitive phenotypes for biomarker identification in mental illness: forward and reverse translation. https://doi.org/10.1007/7854_2018_50
Madison JM, Zhou F, Nigam A, Hussain A, Barker DD, Nehme R et al (2015) Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol Psychiatry 20(6):703–717. https://doi.org/10.1038/mp.2015.7
Maher BJ, LoTurco JJ (2012) Disrupted-in-schizophrenia (DISC1) functions presynaptically at glutamatergic synapses. PLoS One 7(3):e34053. https://doi.org/10.1371/journal.pone.0034053
Malhotra D, Sebat J (2012) CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148(6):1223–1241. https://doi.org/10.1016/j.cell.2012.02.039
Mansour AA, Goncalves JT, Bloyd CW, Li H, Fernandes S, Quang D et al (2018) An in vivo model of functional and vascularized human brain organoids. Nat Biotechnol 36(5):432–441. https://doi.org/10.1038/nbt.4127
Marchetto MC, Belinson H, Tian Y, Freitas BC, Fu C, Vadodaria K et al (2017) Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol Psychiatry 22(6):820–835. https://doi.org/10.1038/mp.2016.95
Mariani J, Coppola G, Zhang P, Abyzov A, Provini L, Tomasini L et al (2015) FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders. Cell 162(2):375–390. https://doi.org/10.1016/j.cell.2015.06.034
Marin O, Muller U (2014) Lineage origins of GABAergic versus glutamatergic neurons in the neocortex. Curr Opin Neurobiol 26:132–141. https://doi.org/10.1016/j.conb.2014.01.015
McCammon JM, Sive H (2015) Addressing the genetics of human mental health disorders in model organisms. Annu Rev Genomics Hum Genet 16:173–197. https://doi.org/10.1146/annurev-genom-090314-050048
Mertens J, Wang QW, Kim Y, Yu DX, Pham S, Yang B et al (2015) Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 527(7576):95–99. https://doi.org/10.1038/nature15526
Meyer KD, Morris JA (2008) Immunohistochemical analysis of Disc1 expression in the developing and adult hippocampus. Gene Expr Patterns 8(7–8):494–501. https://doi.org/10.1016/j.gep.2008.06.005
Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA et al (2000) Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 9(9):1415–1423
Miyoshi K, Honda A, Baba K, Taniguchi M, Oono K, Fujita T et al (2003) Disrupted-in-schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth. Mol Psychiatry 8(7):685–694. https://doi.org/10.1038/sj.mp.4001352
Modabbernia A, Velthorst E, Reichenberg A (2017) Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses. Mol Autism 8:13. https://doi.org/10.1186/s13229-017-0121-4
Mor-Shaked H, Eiges R (2016) Modeling fragile X syndrome using human pluripotent stem cells. Genes 7(10):77. https://doi.org/10.3390/genes7100077
Muguruma K, Nishiyama A, Kawakami H, Hashimoto K, Sasai Y (2015) Self-organization of polarized cerebellar tissue in 3D culture of human pluripotent stem cells. Cell Rep 10(4):537–550. https://doi.org/10.1016/j.celrep.2014.12.051
Nagahara AH, Tuszynski MH (2011) Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 10(3):209–219. https://doi.org/10.1038/nrd3366
Napoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F, De Rubeis S et al (2008) The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134(6):1042–1054. https://doi.org/10.1016/j.cell.2008.07.031
Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A et al (2012) Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485(7397):242–245. https://doi.org/10.1038/nature11011
Need AC, Goldstein DB (2014) Schizophrenia genetics comes of age. Neuron 83(4):760–763. https://doi.org/10.1016/j.neuron.2014.08.015
Niwa M, Kamiya A, Murai R, Kubo K, Gruber AJ, Tomita K et al (2010) Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits. Neuron 65(4):480–489. https://doi.org/10.1016/j.neuron.2010.01.019
Opler M, Charap J, Greig A, Stein V, Polito S, Malaspina D (2013) Environmental risk factors and schizophrenia. Int J Ment Health 42(1):23–32
Ozeki Y, Tomoda T, Kleiderlein J, Kamiya A, Bord L, Fujii K et al (2003) Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci U S A 100(1):289–294. https://doi.org/10.1073/pnas.0136913100
Parr CJC, Yamanaka S, Saito H (2017) An update on stem cell biology and engineering for brain development. Mol Psychiatry 22(6):808–819. https://doi.org/10.1038/mp.2017.66
Pasca SP, Portmann T, Voineagu I, Yazawa M, Shcheglovitov A, Pasca AM et al (2011) Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat Med 17(12):1657–1662. https://doi.org/10.1038/nm.2576
Pasca AM, Sloan SA, Clarke LE, Tian Y, Makinson CD, Huber N et al (2015) Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods 12(7):671–678. https://doi.org/10.1038/nmeth.3415
Pearl JI, Kean LS, Davis MM, Wu JC (2012) Pluripotent stem cells: immune to the immune system? Sci Transl Med 4(164):164ps125. https://doi.org/10.1126/scitranslmed.3005090
Perrier AL, Tabar V, Barberi T, Rubio ME, Bruses J, Topf N et al (2004) Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci U S A 101(34):12543–12548. https://doi.org/10.1073/pnas.0404700101
Petit I, Kesner NS, Karry R, Robicsek O, Aberdam E, Muller FJ et al (2012) Induced pluripotent stem cells from hair follicles as a cellular model for neurodevelopmental disorders. Stem Cell Res 8(1):134–140. https://doi.org/10.1016/j.scr.2011.09.003
Porteous DJ, Thomson PA, Millar JK, Evans KL, Hennah W, Soares DC et al (2014) DISC1 as a genetic risk factor for schizophrenia and related major mental illness: response to Sullivan. Mol Psychiatry 19(2):141–143. https://doi.org/10.1038/mp.2013.160
Pratt JA, Morris B, Dawson N (2018) Deconstructing schizophrenia: advances in preclinical models for biomarker identification. Curr Top Behav Neurosci. https://doi.org/10.1007/7854_2018_48
Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF, Sklar P (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460(7256):748–752. https://doi.org/10.1038/nature08185
Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P et al (2014) A polygenic burden of rare disruptive mutations in schizophrenia. Nature 506(7487):185–190. https://doi.org/10.1038/nature12975
Qian X, Nguyen HN, Song MM, Hadiono C, Ogden SC, Hammack C et al (2016) Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165(5):1238–1254. https://doi.org/10.1016/j.cell.2016.04.032
Quadrato G, Nguyen T, Macosko EZ, Sherwood JL, Min Yang S, Berger DR et al (2017) Cell diversity and network dynamics in photosensitive human brain organoids. Nature 545(7652):48–53. https://doi.org/10.1038/nature22047
Ranga A, Girgin M, Meinhardt A, Eberle D, Caiazzo M, Tanaka EM, Lutolf MP (2016) Neural tube morphogenesis in synthetic 3D microenvironments. Proc Natl Acad Sci U S A 113(44):E6831–E6839. https://doi.org/10.1073/pnas.1603529113
Richards RI, Sutherland GR (1992) Dynamic mutations: a new class of mutations causing human disease. Cell 70(5):709–712
Ripke S, O'Dushlaine C, Chambert K, Moran JL, Kahler AK, Akterin S et al (2013) Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet 45(10):1150–1159. https://doi.org/10.1038/ng.2742
Ronald A, Hoekstra RA (2011) Autism spectrum disorders and autistic traits: a decade of new twin studies. Am J Med Genet B Neuropsychiatr Genet 156B(3):255–274. https://doi.org/10.1002/ajmg.b.31159
Sakaguchi H, Kadoshima T, Soen M, Narii N, Ishida Y, Ohgushi M et al (2015) Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat Commun 6:8896. https://doi.org/10.1038/ncomms9896
Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ et al (2012) De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485(7397):237–241. https://doi.org/10.1038/nature10945
Scattoni ML, McFarlane HG, Zhodzishsky V, Caldwell HK, Young WS, Ricceri L, Crawley JN (2008) Reduced ultrasonic vocalizations in vasopressin 1b knockout mice. Behav Brain Res 187(2):371–378. https://doi.org/10.1016/j.bbr.2007.09.034
Schenck A, Bardoni B, Moro A, Bagni C, Mandel JL (2001) A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P. Proc Natl Acad Sci U S A 98(15):8844–8849. https://doi.org/10.1073/pnas.151231598
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511(7510):421–427. https://doi.org/10.1038/nature13595
Schneider M, Debbane M, Bassett AS, Chow EW, Fung WL, van den Bree M et al (2014) Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome. Am J Psychiatry 171(6):627–639. https://doi.org/10.1176/appi.ajp.2013.13070864
Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N et al (2016) Schizophrenia risk from complex variation of complement component 4. Nature 530(7589):177–183. https://doi.org/10.1038/nature16549
Shen S, Lang B, Nakamoto C, Zhang F, Pu J, Kuan SL et al (2008) Schizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated Disc1. J Neurosci 28(43):10893–10904. https://doi.org/10.1523/JNEUROSCI.3299-08.2008
Silverman JL, Yang M, Lord C, Crawley JN (2010) Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci 11(7):490–502. https://doi.org/10.1038/nrn2851
Srikanth P, Han K, Callahan DG, Makovkina E, Muratore CR, Lalli MA et al (2015) Genomic DISC1 disruption in hiPSCs alters Wnt signaling and neural cell fate. Cell Rep 12(9):1414–1429. https://doi.org/10.1016/j.celrep.2015.07.061
St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G et al (1990) Association within a family of a balanced autosomal translocation with major mental illness. Lancet 336(8706):13–16
Staerk J, Dawlaty MM, Gao Q, Maetzel D, Hanna J, Sommer CA et al (2010) Reprogramming of human peripheral blood cells to induced pluripotent stem cells. Cell Stem Cell 7(1):20–24. https://doi.org/10.1016/j.stem.2010.06.002
Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A, Steinberg S et al (2008) Large recurrent microdeletions associated with schizophrenia. Nature 455(7210):232–236. https://doi.org/10.1038/nature07229
Stefansson H, Meyer-Lindenberg A, Steinberg S, Magnusdottir B, Morgen K, Arnarsdottir S et al (2014) CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature 505(7483):361–366. https://doi.org/10.1038/nature12818
Steffen A, Rottner K, Ehinger J, Innocenti M, Scita G, Wehland J, Stradal TE (2004) Sra-1 and Nap1 link Rac to actin assembly driving lamellipodia formation. EMBO J 23(4):749–759. https://doi.org/10.1038/sj.emboj.7600084
Strauss KA, Puffenberger EG, Huentelman MJ, Gottlieb S, Dobrin SE, Parod JM et al (2006) Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med 354(13):1370–1377. https://doi.org/10.1056/NEJMoa052773
Sullivan PF (2013) Questions about DISC1 as a genetic risk factor for schizophrenia. Mol Psychiatry 18(10):1050–1052. https://doi.org/10.1038/mp.2012.182
Sullivan PF, Kendler KS, Neale MC (2003) Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 60(12):1187–1192. https://doi.org/10.1001/archpsyc.60.12.1187
Tabata H (2015) Diverse subtypes of astrocytes and their development during corticogenesis. Front Neurosci 9:114. https://doi.org/10.3389/fnins.2015.00114
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. https://doi.org/10.1016/j.cell.2006.07.024
Takahashi K, Yamanaka S (2016) A decade of transcription factor-mediated reprogramming to pluripotency. Nat Rev Mol Cell Biol 17(3):183–193. https://doi.org/10.1038/nrm.2016.8
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. https://doi.org/10.1016/j.cell.2007.11.019
Takayanagi Y, Yoshida M, Bielsky IF, Ross HE, Kawamata M, Onaka T et al (2005) Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice. Proc Natl Acad Sci U S A 102(44):16096–16101. https://doi.org/10.1073/pnas.0505312102
Tam GW, van de Lagemaat LN, Redon R, Strathdee KE, Croning MD, Malloy MP et al (2010) Confirmed rare copy number variants implicate novel genes in schizophrenia. Biochem Soc Trans 38(2):445–451. https://doi.org/10.1042/BST0380445
Tang W, Thevathasan JV, Lin Q, Lim KB, Kuroda K, Kaibuchi K et al (2016) Stimulation of synaptic vesicle exocytosis by the mental disease gene DISC1 is mediated by N-type voltage-gated calcium channels. Front Synaptic Neurosci 8:15. https://doi.org/10.3389/fnsyn.2016.00015
Tao Y, Zhou X, Liu D, Li H, Liang C, Li F, Chen Q (2016) Proportion of collagen type II in the extracellular matrix promotes the differentiation of human adipose-derived mesenchymal stem cells into nucleus pulposus cells. Biofactors 42(2):212–223. https://doi.org/10.1002/biof.1266
Tomoda T, Sumitomo A, Jaaro-Peled H, Sawa A (2016) Utility and validity of DISC1 mouse models in biological psychiatry. Neuroscience 321:99–107. https://doi.org/10.1016/j.neuroscience.2015.12.061
Vadivelu RK, Kamble H, Shiddiky MJA, Nguyen N-T (2017) Microfluidic Technology for the Generation of cell spheroids and their applications. Micromachines 8(4):94. https://doi.org/10.3390/mi8040094
Vadodaria KC, Mertens J, Paquola A, Bardy C, Li X, Jappelli R et al (2016) Generation of functional human serotonergic neurons from fibroblasts. Mol Psychiatry 21(1):49–61. https://doi.org/10.1038/mp.2015.161
van den Ameele J, Tiberi L, Vanderhaeghen P, Espuny-Camacho I (2014) Thinking out of the dish: what to learn about cortical development using pluripotent stem cells. Trends Neurosci 37(6):334–342. https://doi.org/10.1016/j.tins.2014.03.005
Wang S, Bates J, Li X, Schanz S, Chandler-Militello D, Levine C et al (2013) Human iPSC-derived oligodendrocyte progenitor cells can myelinate and rescue a mouse model of congenital hypomyelination. Cell Stem Cell 12(2):252–264. https://doi.org/10.1016/j.stem.2012.12.002
Wang JL, Shamah SM, Sun AX, Waldman ID, Haggarty SJ, Perlis RH (2014) Label-free, live optical imaging of reprogrammed bipolar disorder patient-derived cells reveals a functional correlate of lithium responsiveness. Transl Psychiatry 4:e428. https://doi.org/10.1038/tp.2014.72
Watanabe K, Kamiya D, Nishiyama A, Katayama T, Nozaki S, Kawasaki H et al (2005) Directed differentiation of telencephalic precursors from embryonic stem cells. Nat Neurosci 8(3):288–296. https://doi.org/10.1038/nn1402
Wei WH, Hemani G, Haley CS (2014) Detecting epistasis in human complex traits. Nat Rev Genet 15(11):722–733. https://doi.org/10.1038/nrg3747
Wen Z, Nguyen HN, Guo Z, Lalli MA, Wang X, Su Y et al (2014) Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515(7527):414–418. https://doi.org/10.1038/nature13716
Whalley HC, Dimitrova R, Sprooten E, Dauvermann MR, Romaniuk L, Duff B et al (2015) Effects of a balanced translocation between chromosomes 1 and 11 disrupting the DISC1 locus on white matter integrity. PLoS One 10(6):e0130900. https://doi.org/10.1371/journal.pone.0130900
Windrem MS, Osipovitch M, Liu Z, Bates J, Chandler-Militello D, Zou L et al (2017) Human iPSC glial mouse chimeras reveal glial contributions to schizophrenia. Cell Stem Cell 21(2):195–208. https://doi.org/10.1016/j.stem.2017.06.012
Xu Z, Jiang H, Zhong P, Yan Z, Chen S, Feng J (2016) Direct conversion of human fibroblasts to induced serotonergic neurons. Mol Psychiatry 21(1):62–70. https://doi.org/10.1038/mp.2015.101
Ye F, Kang E, Yu C, Qian X, Jacob F, Yu C et al (2017) DISC1 regulates neurogenesis via modulating kinetochore attachment of Ndel1/Nde1 during mitosis. Neuron 96(5):1041–1054. https://doi.org/10.1016/j.neuron.2017.10.010
Yerabham ASK, Mas PJ, Decker C, Soares DC, Weiergraber OH, Nagel-Steger L et al (2017) A structural organization for the disrupted in schizophrenia 1 protein, identified by high-throughput screening, reveals distinctly folded regions, which are bisected by mental illness-related mutations. J Biol Chem 292(16):6468–6477. https://doi.org/10.1074/jbc.M116.773903
Yoon KJ, Nguyen HN, Ursini G, Zhang F, Kim NS, Wen Z et al (2014) Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity. Cell Stem Cell 15(1):79–91. https://doi.org/10.1016/j.stem.2014.05.003
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917–1920. https://doi.org/10.1126/science.1151526
Zhao WN, Cheng C, Theriault KM, Sheridan SD, Tsai LH, Haggarty SJ (2012) A high-throughput screen for Wnt/beta-catenin signaling pathway modulators in human iPSC-derived neural progenitors. J Biomol Screen 17(9):1252–1263. https://doi.org/10.1177/1087057112456876
Zhao Q, Li T, Zhao X, Huang K, Wang T, Li Z et al (2013) Rare CNVs and tag SNPs at 15q11.2 are associated with schizophrenia in the Han Chinese population. Schizophr Bull 39(3):712–719. https://doi.org/10.1093/schbul/sbr197
Acknowledgements
MJ is funded by a Wellcome Trust Clinical postdoctoral research fellowship, The Sackler Foundation, The RS Macdonald Trust, and The Simons Initiative for the Developing Brain. RFH is a Wellcome Trust-funded translational neuroscience PhD student.
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Johnstone, M., Hillary, R.F., St. Clair, D. (2018). Stem Cells to Inform the Neurobiology of Mental Illness. In: Pratt, J., Hall, J. (eds) Biomarkers in Psychiatry. Current Topics in Behavioral Neurosciences, vol 40. Springer, Cham. https://doi.org/10.1007/7854_2018_57
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