Recent advances in cell reprogramming enable investigators to generate pluripotent stem cells from somatic cells. These induced pluripotent cells can subsequently be differentiated into any cell type, making it possible for the first time to obtain functional human neurons in the lab from control subjects and patients with psychiatric disorders. In this review, we survey the progress made in generating various neuronal subtypes in vitro, with special emphasis on the characterization of these neurons and the identification of unique features of human brain development in a dish. We also discuss efforts to uncover neuronal phenotypes from patients with psychiatric disease and prospects for the use of this platform for drug development.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Akbarian S, Huang HS. 2006. Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders. Brain Res. Rev. 52:293–304 [Google Scholar]
  2. Alcamo EA, Chirivella L, Dautzenberg M, Dobreva G, Farinas I. et al. 2008. Satb2 regulates callosal projection neuron identity in the developing cerebral cortex. Neuron 57:364–77 [Google Scholar]
  3. Allman JM, Tetreault NA, Hakeem AY, Manaye KF, Semendeferi K. et al. 2011. The von Economo neurons in the frontoinsular and anterior cingulate cortex. Ann. N. Y. Acad. Sci. 1225:59–71 [Google Scholar]
  4. Allman JM, Watson KK, Tetreault NA, Hakeem AY. 2005. Intuition and autism: a possible role for Von Economo neurons. Trends Cogn. Sci. 9:367–73 [Google Scholar]
  5. Altmann CR, Brivanlou AH. 2001. Neural patterning in the vertebrate embryo. Int. Rev. Cytol. 203:447–82 [Google Scholar]
  6. Amoroso MW, Croft GF, Williams DJ, O'Keeffe S, Carrasco MA. et al. 2013. Accelerated high-yield generation of limb-innervating motor neurons from human stem cells. J. Neurosci. 33:574–86 [Google Scholar]
  7. Anokye-Danso F, Trivedi CM, Juhr D, Gupta M, Cui Z. et al. 2011. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell 8:376–88 [Google Scholar]
  8. Arlotta P, Molyneaux BJ, Chen J, Inoue J, Kominami R, Macklis JD. 2005. Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron 45:207–21 [Google Scholar]
  9. Ascoli GA, Alonso-Nanclares L, Anderson SA, Barrionuevo G, Benavides-Piccione R. et al. 2008. Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat. Rev. 9:557–68 [Google Scholar]
  10. Aubry L, Bugi A, Lefort N, Rousseau F, Peschanski M, Perrier AL. 2008. Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats. Proc. Natl. Acad. Sci. USA 105:16707–12 [Google Scholar]
  11. Barberi T, Klivenyi P, Calingasan NY, Lee H, Kawamata H. et al. 2003. Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice. Nat. Biotechnol. 21:1200–7 [Google Scholar]
  12. Benavides-Piccione R, Ballesteros-Yañez I, DeFelipe J, Yuste R. 2002. Cortical area and species differences in dendritic spine morphology. J. Neurocytol. 31:337–46 [Google Scholar]
  13. Betizeau M, Cortay V, Patti D, Pfister S, Gautier E. et al. 2013. Precursor diversity and complexity of lineage relationships in the outer subventricular zone of the primate. Neuron 80:442–57 [Google Scholar]
  14. Bilican B, Serio A, Barmada SJ, Nishimura AL, Sullivan GJ. et al. 2012. Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proc. Natl. Acad. Sci. USA 109:5803–8 [Google Scholar]
  15. Brain Work. Group 2013. Advisory Committee to the NIH Director: Interim Report Bethesda, MD: Natl. Inst. Health http://www.nih.gov/science/brain/09162013-Interim%20Report_Final%20Composite.pdf [Google Scholar]
  16. Britanova O, de Juan Romero C, Cheung A, Kwan KY, Schwark M. et al. 2008. Satb2 is a postmitotic determinant for upper-layer neuron specification in the neocortex. Neuron 57:378–92 [Google Scholar]
  17. Brüne M, Schöbel A, Karau R, Benali A, Faustmann PM. et al. 2010. Von Economo neuron density in the anterior cingulate cortex is reduced in early onset schizophrenia. Acta Neuropathol. 119:771–78 [Google Scholar]
  18. Caiazzo M, Dell'Anno MT, Dvoretskova E, Lazarevic D, Taverna S. et al. 2011. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476:224–27 [Google Scholar]
  19. Carri AD, Onorati M, Lelos MJ, Castiglioni V, Faedo A. et al. 2013. Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons. Development 140:301–12 [Google Scholar]
  20. Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L. 2009. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol. 27:275–80 [Google Scholar]
  21. Chambers SM, Qi Y, Mica Y, Lee G, Zhang XJ. et al. 2012. Combined small-molecule inhibition accelerates developmental timing and converts human pluripotent stem cells into nociceptors. Nat. Biotechnol. 30:715–20 [Google Scholar]
  22. Chao H-T, Chen H, Samaco RC, Xue M, Chahrour M. et al. 2010. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468:263–69 [Google Scholar]
  23. Charrier C, Joshi K, Coutinho-Budd J, Kim J-E, Lambert N. et al. 2012. Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation. Cell 149:923–35 [Google Scholar]
  24. Chen B, Schaevitz LR, McConnell SK. 2005. Fezl regulates the differentiation and axon targeting of layer 5 subcortical projection neurons in cerebral cortex. Proc. Natl. Acad. Sci. USA 102:17184–89 [Google Scholar]
  25. Chen B, Wang SS, Hattox AM, Rayburn H, Nelson SB, McConnell SK. 2008. The Fezf2-Ctip2 genetic pathway regulates the fate choice of subcortical projection neurons in the developing cerebral cortex. Proc. Natl. Acad. Sci. USA 105:11382–87 [Google Scholar]
  26. Cheung AY, Horvath LM, Grafodatskaya D, Pasceri P, Weksberg R. et al. 2011. Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation. Hum. Mol. Genet. 20:2103–15 [Google Scholar]
  27. Chung CY, Khurana V, Auluck PK, Tardiff DF, Mazzulli JR. et al. 2013. Identification and rescue of α-synuclein toxicity in Parkinson patient–derived neurons. Science 342:983–87 [Google Scholar]
  28. Cobos I, Seeley WW. 2013. Human von Economo neurons express transcription factors associated with layer V subcerebral projection neurons. Cereb. Cortex. In press [Google Scholar]
  29. Coovert DD, Le TT, McAndrew PE, Strasswimmer J, Crawford TO. et al. 1997. The survival motor neuron protein in spinal muscular atrophy. Hum. Mol. Genet. 6:1205–14 [Google Scholar]
  30. Coufal NG, Garcia-Perez JL, Peng GE, Yeo GW, Mu Y. et al. 2009. L1 retrotransposition in human neural progenitor cells. Nature 460:1127–31 [Google Scholar]
  31. Crossley PH, Martinez S, Martin GR. 1996. Midbrain development induced by FGF8 in the chick embryo. Nature 380:66–68 [Google Scholar]
  32. Cubelos B, Sebastian-Serrano A, Beccari L, Calcagnotto ME, Cisneros E. et al. 2010. Cux1 and Cux2 regulate dendritic branching, spine morphology, and synapses of the upper layer neurons of the cortex. Neuron 66:523–35 [Google Scholar]
  33. Danjo T, Eiraku M, Muguruma K, Watanabe K, Kawada M. et al. 2011. Subregional specification of embryonic stem cell-derived ventral telencephalic tissues by timed and combinatory treatment with extrinsic signals. J. Neurosci. 31:1919–33 [Google Scholar]
  34. DeFelipe J. 2011. The evolution of the brain, the human nature of cortical circuits, and intellectual creativity. Front. Neuroanat. 5:29 [Google Scholar]
  35. DeFelipe J, Ballesteros-Yañez I, Inda MC, Muñoz A. 2006. Double-bouquet cells in the monkey and human cerebral cortex with special reference to areas 17 and 18. Prog. Brain Res. 154:15–32 [Google Scholar]
  36. DeFelipe J, López-Cruz PL, Benavides-Piccione R, Bielza C, Larrañaga P. et al. 2013. New insights into the classification and nomenclature of cortical GABAergic interneurons. Nat. Rev. 14:202–16 [Google Scholar]
  37. Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H. et al. 2008. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321:1218–21 [Google Scholar]
  38. Ebert AD, Yu J, Rose FF Jr, Mattis VB, Lorson CL. et al. 2009. Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457:277–80 [Google Scholar]
  39. Eberwine J, Lovatt D, Buckley P, Dueck H, Francis C. et al. 2012. Quantitative biology of single neurons. J. R. Soc. Interface 9:3165–83 [Google Scholar]
  40. Egawa N, Kitaoka S, Tsukita K, Naitoh M, Takahashi K. et al. 2012. Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci. Transl. Med. 4:145ra04 [Google Scholar]
  41. Eiraku M, Watanabe K, Matsuo-Takasaki M, Kawada M, Yonemura S. et al. 2008. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 3:519–32 [Google Scholar]
  42. Elkabetz Y, Panagiotakos G, Al Shamy G, Socci ND, Tabar V, Studer L. 2008. Human ES cell-derived neural rosettes reveal a functionally distinct early neural stem cell stage. Genes Dev. 22:152–65 [Google Scholar]
  43. Erceg S, Lukovic D, Moreno-Manzano V, Stojkovic M, Bhattacharya SS. 2012. Derivation of cerebellar neurons from human pluripotent stem cells. Curr. Protoc. Stem Cell Biol. 20:1H.5–10 [Google Scholar]
  44. Espuny-Camacho I, Michelsen KA, Gall D, Linaro D, Hasche A. et al. 2013. Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo. Neuron 77:440–56 [Google Scholar]
  45. Falk S, Sommer L. 2009. Stage- and area-specific control of stem cells in the developing nervous system. Curr. Opin. Genet. Dev. 19:454–60 [Google Scholar]
  46. Farkas LM, Huttner WB. 2008. The cell biology of neural stem and progenitor cells and its significance for their proliferation versus differentiation during mammalian brain development. Curr. Opin. Cell Biol. 20:707–15 [Google Scholar]
  47. Fasano CA, Chambers SM, Lee G, Tomishima MJ, Studer L. 2010. Efficient derivation of functional floor plate tissue from human embryonic stem cells. Cell Stem Cell 6:336–47 [Google Scholar]
  48. Fietz SA, Kelava I, Vogt J, Wilsch-Bräuninger M, Stenzel D. et al. 2010. OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling. Nat. Neurosci. 13:690–99 [Google Scholar]
  49. Fu X, Giavalisco P, Liu X, Catchpole G, Fu N. et al. 2011. Rapid metabolic evolution in human prefrontal cortex. Proc. Natl. Acad. Sci. USA 108:6181–86 [Google Scholar]
  50. Ganat YM, Calder EL, Kriks S, Nelander J, Tu EY. et al. 2012. Identification of embryonic stem cell-derived midbrain dopaminergic neurons for engraftment. J. Clin. Investig. 122:2928–39 [Google Scholar]
  51. Gaspar P, Berger B, Febvret A, Vigny A, Krieger-Poulet M, Borri-Voltattorni C. 1987. Tyrosine hydroxylase-immunoreactive neurons in the human cerebral cortex: a novel catecholaminergic group?. Neurosci. Lett. 80:257–62 [Google Scholar]
  52. Greig LC, Woodworth MB, Galazo MJ, Padmanabhan H, Macklis JD. 2013. Molecular logic of neocortical projection neuron specification, development and diversity. Nat. Rev. Neurosci. 14:755–69 [Google Scholar]
  53. Hansen DV, Lui JH, Parker PRL, Kriegstein AR. 2010. Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature 464:554–61 [Google Scholar]
  54. HD iPSC Consort 2012. Induced pluripotent stem cells from patients with Huntington's disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell 11:264–78 [Google Scholar]
  55. Hevner RF, Shi L, Justice N, Hsueh Y, Sheng M. et al. 2001. Tbr1 regulates differentiation of the preplate and layer 6. Neuron 29:353–66 [Google Scholar]
  56. Hobert O. 2011. Regulation of terminal differentiation programs in the nervous system. Annu. Rev. Cell Dev. Biol. 27:681–96 [Google Scholar]
  57. Hornung JP, Törk I, De Tribolet N. 1989. Morphology of tyrosine hydroxylase-immunoreactive neurons in the human cerebral cortex. Exp. Brain Res. 76:12–20 [Google Scholar]
  58. Hynes M, Porter JA, Chiang C, Chang D, Tessier-Lavigne M. et al. 1995. Induction of midbrain dopaminergic neurons by Sonic hedgehog. Neuron 15:35–44 [Google Scholar]
  59. Kamiya D, Banno S, Sasai N, Ohgushi M, Inomata H. et al. 2011. Intrinsic transition of embryonic stem-cell differentiation into neural progenitors. Nature 470:503–9 [Google Scholar]
  60. Kawasaki H, Mizuseki K, Nishikawa S, Kaneko S, Kuwana Y. et al. 2000. Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. Neuron 28:31–40 [Google Scholar]
  61. Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y. et al. 2013. Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. Cell Stem Cell 12:487–96 [Google Scholar]
  62. Krey JF, Paşca SP, Shcheglovitov A, Yazawa M, Schwemberger R. et al. 2013. Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nat. Neurosci. 16:201–9 [Google Scholar]
  63. Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR. et al. 2011. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 480:547–51 [Google Scholar]
  64. Kwan KY, Lam MM, Johnson MB, Dube U, Shim S. et al. 2012. Species-dependent posttranscriptional regulation of NOS1 by FMRP in the developing cerebral cortex. Cell 149:899–911 [Google Scholar]
  65. Lai T, Jabaudon D, Molyneaux BJ, Azim E, Arlotta P. et al. 2008. SOX5 controls the sequential generation of distinct corticofugal neuron subtypes. Neuron 57:232–47 [Google Scholar]
  66. LaMonica BE, Lui JH, Wang X, Kriegstein AR. 2012. OSVZ progenitors in the human cortex: an updated perspective on neurodevelopmental disease. Curr. Opin. Neurobiol. 22:747–53 [Google Scholar]
  67. Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS. et al. 2013. Cerebral organoids model human brain development and microcephaly. Nature 501:373–79 [Google Scholar]
  68. Le Dréau G, Martí E. 2012. Dorsal-ventral patterning of the neural tube: a tale of three signals. Dev. Neurobiol. 72:1471–81 [Google Scholar]
  69. Le Magueresse C, Monyer H. 2013. GABAergic interneurons shape the functional maturation of the cortex. Neuron 77:388–405 [Google Scholar]
  70. Lee G, Kim H, Elkabetz Y, Al Shamy G, Panagiotakos G. et al. 2007a. Isolation and directed differentiation of neural crest stem cells derived from human embryonic stem cells. Nat. Biotechnol. 25:1468–75 [Google Scholar]
  71. Lee G, Papapetrou EP, Kim H, Chambers SM, Tomishima MJ. et al. 2009. Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 461:402–6 [Google Scholar]
  72. Lee G, Ramirez CN, Kim H, Zeltner N, Liu B. et al. 2012. Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression. Nat. Biotechnol. 30:1244–48 [Google Scholar]
  73. Lee H, Shamy GA, Elkabetz Y, Schofield CM, Harrsion NL. et al. 2007b. Directed differentiation and transplantation of human embryonic stem cell-derived motoneurons. Stem Cells 25:1931–39 [Google Scholar]
  74. Lee S-H, Lumelsky N, Studer L, Auerbach JM, McKay RD. 2000. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat. Biotechnol. 18:675–79 [Google Scholar]
  75. Leone DP, Srinivasan K, Chen B, Alcamo E, McConnell SK. 2008. The determination of projection neuron identity in the developing cerebral cortex. Curr. Opin. Neurobiol. 18:28–35 [Google Scholar]
  76. Lewis DA, Curley AA, Glausier JR, Volk DW. 2012. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 35:57–67 [Google Scholar]
  77. Li XJ, Zhang X, Johnson MA, Wang ZB, Lavaute T, Zhang SC. 2009. Coordination of sonic hedgehog and Wnt signaling determines ventral and dorsal telencephalic neuron types from human embryonic stem cells. Development 136:4055–63 [Google Scholar]
  78. Lu B, Jan L, Jan Y-N. 2000. Control of cell divisions in the nervous system: symmetry and asymmetry. Annu. Rev. Neurosci. 23:531–56 [Google Scholar]
  79. Lui JH, Hansen DV, Kriegstein AR. 2011. Development and evolution of the human neocortex. Cell 146:18–36 [Google Scholar]
  80. Ma L, Hu B, Liu Y, Vermilyea SC, Liu H. et al. 2012. Human embryonic stem cell-derived GABA neurons correct locomotion deficits in quinolinic acid-lesioned mice. Cell Stem Cell 10:455–64 [Google Scholar]
  81. Mackler SA, Brooks BP, Eberwine JH. 1992. Stimulus-induced coordinate changes in mRNA abundance in single postsynaptic hippocampal CA1 neurons. Neuron 9:539–48 [Google Scholar]
  82. Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW. et al. 2010. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143:527–39 [Google Scholar]
  83. Marchetto MC, Muotri AR, Mu Y, Smith AM, Cezar GG, Gage FH. 2008. Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 3:649–57 [Google Scholar]
  84. Marchetto MC, Narvaiza I, Denli AM, Benner C, Lazzarini TA. et al. 2013. Differential L1 regulation in pluripotent stem cells of humans and apes. Nature 503:525–29 [Google Scholar]
  85. Maroof AM, Brown K, Shi SH, Studer L, Anderson SA. 2010. Prospective isolation of cortical interneuron precursors from mouse embryonic stem cells. J. Neurosci. 30:4667–75 [Google Scholar]
  86. Maroof AM, Keros S, Tyson JA, Ying SW, Ganat YM. et al. 2013. Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell 12:559–72 [Google Scholar]
  87. Meyer-Lindenberg A, Weinberger DR. 2006. Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat. Rev. Neurosci. 7:818–27 [Google Scholar]
  88. Migliore M, Shepherd GM. 2005. Opinion: an integrated approach to classifying neuronal phenotypes. Nat. Rev. Neurosci. 6:810–18 [Google Scholar]
  89. Mione MC, Cavanagh JF, Harris B, Parnavelas JG. 1997. Cell fate specification and symmetrical/asymmetrical divisions in the developing cerebral cortex. J. Neurosci. 17:2018–29 [Google Scholar]
  90. Molnár G, Oláh S, Komlósi G, Füle M, Szabadics J. et al. 2008. Complex events initiated by individual spikes in the human cerebral cortex. PLOS Biol. 6:9e222 [Google Scholar]
  91. Molyneaux BJ, Arlotta P, Fame RM, MacDonald JL, MacQuarrie KL, Macklis JD. 2009. Novel subtype-specific genes identify distinct subpopulations of callosal projection neurons. J. Neurosci. 29:12343–54 [Google Scholar]
  92. Molyneaux BJ, Arlotta P, Hirata T, Hibi M, Macklis JD. 2005. Fezl is required for the birth and specification of corticospinal motor neurons. Neuron 47:817–31 [Google Scholar]
  93. Muotri AR, Chu VT, Marchetto MCN, Deng W, Moran JV, Gage FH. 2005. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435:903–10 [Google Scholar]
  94. Muotri AR, Marchetto MC, Coufal NG, Oefner R, Yeo G. et al. 2010. L1 retrotransposition in neurons is modulated by MeCP2. Nature 468:443–46 [Google Scholar]
  95. Nguyen HN, Byers B, Cord B, Shcheglovitov A, Byrne J. et al. 2011. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8:267–80 [Google Scholar]
  96. Nicholas CR, Chen J, Tang Y, Southwell DG, Chalmers N. et al. 2013. Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell 12:573–86 [Google Scholar]
  97. Noctor SC, Flint AC, Weissman TA, Wong WS, Clinton BK, Kriegstein AR. 2002. Dividing precursor cells of the embryonic cortical ventricular zone have morphological and molecular characteristics of radial glia. J. Neurosci. 22:3161–73 [Google Scholar]
  98. Noctor SC, Martínez-Cerdeño V, Ivic L, Kriegstein AR. 2004. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat. Neurosci. 7:136–44 [Google Scholar]
  99. Oberheim NA, Takano T, Han X, He W, Lin JH. et al. 2009. Uniquely hominid features of adult human astrocytes. J. Neurosci. 29:3276–87 [Google Scholar]
  100. Okano H, Temple S. 2009. Cell types to order: temporal specification of CNS stem cells. Curr. Opin. Neurobiol. 19:112–19 [Google Scholar]
  101. Onder TT, Kara N, Cherry A, Sinha AU, Zhu N. et al. 2012. Chromatin-modifying enzymes as modulators of reprogramming. Nature 483:598–602 [Google Scholar]
  102. Owens DF, Kriegstein AR. 2002. Is there more to GABA than synaptic inhibition?. Nat. Rev. Neurosci. 3:715–27 [Google Scholar]
  103. Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR. et al. 2011. Induction of human neuronal cells by defined transcription factors. Nature 476:220–23 [Google Scholar]
  104. Park IH, Zhao R, West JA, Yabuuchi A, Huo H. et al. 2008. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451:141–46 [Google Scholar]
  105. Paşca SP, Portmann T, Voineagu I, Yazawa M, Shcheglovitov A. et al. 2011. Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat. Med. 17:1657–62 [Google Scholar]
  106. Peljto M, Wichterle H. 2011. Programming embryonic stem cells to neuronal subtypes. Curr. Opin. Neurobiol. 21:43–51 [Google Scholar]
  107. Perrier AL, Tabar V, Barberi T, Rubio ME, Bruses J. et al. 2004. Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc. Natl. Acad. Sci. USA 101:12543–48 [Google Scholar]
  108. Qiu S, Luo S, Evgrafov O, Li R, Schroth GP. et al. 2012. Single-neuron RNA-Seq: technical feasibility and reproducibility. Front. Genet. 3:124 [Google Scholar]
  109. Rais Y, Zviran A, Geula S, Gafni O, Chomsky E. et al. 2013. Deterministic direct reprogramming of somatic cells to pluripotency. Nature 502:65–70 [Google Scholar]
  110. Ramón y Cajal S. 1899. La textura del sistema nerviosa del hombre y los vertebrados Madrid: Imprenta y Librería de Nicolás Moya [Google Scholar]
  111. Ricciardi S, Ungaro F, Hambrock M, Rademacher N, Stefanelli G. et al. 2012. CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons. Nat. Cell Biol. 14:911–23 [Google Scholar]
  112. Rice J. 2012. Animal models: not close enough. Nature 484:S9 [Google Scholar]
  113. Roy NS, Cleren C, Singh SK, Yang L, Beal MF, Goldman SA. 2006. Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat. Med. 12:1259–68 [Google Scholar]
  114. Santos M, Uppal N, Butti C, Wicinski B, Schmeidler J. et al. 2011. Von Economo neurons in autism: a stereologic study of the frontoinsular cortex in children. Brain Res. 1380:206–17 [Google Scholar]
  115. Seeley WW, Carlin DA, Allman JM, Macedo MN, Bush C. et al. 2006. Early frontotemporal dementia targets neurons unique to apes and humans. Ann. Neurol. 60:660–67 [Google Scholar]
  116. Serio A, Bilican B, Barmada SJ, Ando DM, Zhao C. et al. 2013. Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. Proc. Natl. Acad. Sci. USA 110:4697–702 [Google Scholar]
  117. Shcheglovitov A, Shcheglovitova O, Yazawa M, Portmann T, Shu R. et al. 2013. SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature 503:267–71 [Google Scholar]
  118. Sherwood CC, Stimpson CD, Raghanti MA, Wildman DE, Uddin M. et al. 2006. Evolution of increased glia-neuron ratios in the human frontal cortex. Proc. Natl. Acad. Sci. USA 103:13606–11 [Google Scholar]
  119. Shi Y, Kirwan P, Smith J, MacLean G, Orkin SH, Livesey FJ. 2012a. A human stem cell model of early Alzheimer's disease pathology in Down syndrome. Sci. Transl. Med. 4:124ra29 [Google Scholar]
  120. Shi Y, Kirwan P, Smith J, Robinson HPC, Livesey FJ. 2012b. Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat. Neurosci. 15:477–86, S1 [Google Scholar]
  121. Soldner F, Hockemeyer D, Beard C, Gao Q, Bell GW. et al. 2009. Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136:964–77 [Google Scholar]
  122. Son EY, Ichida JK, Wainger BJ, Toma JS, Rafuse VF. et al. 2011. Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell 9:205–18 [Google Scholar]
  123. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P. et al. 2004. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119:19–31 [Google Scholar]
  124. Spruston N. 2008. Pyramidal neurons: dendritic structure and synaptic integration. Nat. Rev. Neurosci. 9:206–21 [Google Scholar]
  125. Srinivasan K, Leone DP, Bateson RK, Dobreva G, Kohwi Y. et al. 2012. A network of genetic repression and derepression specifies projection fates in the developing neocortex. Proc. Natl. Acad. Sci. USA 109:19071–78 [Google Scholar]
  126. Tabar V, Tomishima M, Panagiotakos G, Wakayama S, Menon J. et al. 2008. Therapeutic cloning in individual parkinsonian mice. Nat. Med. 14:379–81 [Google Scholar]
  127. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T. et al. 2007. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–72 [Google Scholar]
  128. Tiberi L, Vanderhaeghen P, van den Ameele J. 2012. Cortical neurogenesis and morphogens: diversity of cues, sources and functions. Curr. Opin. Cell Biol. 24:269–76 [Google Scholar]
  129. Toledo-Rodriguez M, Blumenfeld B, Wu C, Luo J, Attali B. et al. 2004. Correlation maps allow neuronal electrical properties to be predicted from single-cell gene expression profiles in rat neocortex. Cereb. Cortex 14:1310–27 [Google Scholar]
  130. Tropepe V, Hitoshi S, Sirard C, Mak TW, Rossant J, van der Kooy D. 2001. Direct neural fate specification from embryonic stem cells: a primitive mammalian neural stem cell stage acquired through a default mechanism. Neuron 30:65–78 [Google Scholar]
  131. Trottier S, Geffard M, Evrard B. 1989. Co-localization of tyrosine hydroxylase and GABA immunoreactivities in human cortical neurons. Neurosci. Lett. 106:76–82 [Google Scholar]
  132. van der Worp HB, Howells DW, Sena ES, Porritt MJ, Rewell S. et al. 2010. Can animal models of disease reliably inform human studies. PLOS Med. 7:e1000245 [Google Scholar]
  133. Warren L, Manos PD, Ahfeldt T, Loh YH, Li H. et al. 2010. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7:618–30 [Google Scholar]
  134. Watanabe K, Kamiya D, Nishiyama A, Katayama T, Nozaki S. et al. 2005. Directed differentiation of telencephalic precursors from embryonic stem cells. Nat. Neurosci. 8:288–96 [Google Scholar]
  135. Wonders CP, Anderson SA. 2006. The origin and specification of cortical interneurons. Nat. Rev. Neurosci. 7:687–96 [Google Scholar]
  136. Yang YM, Gupta SK, Kim KJ, Powers BE, Cerqueira A. et al. 2013. A small molecule screen in stem-cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic for ALS. Cell Stem Cell 12:713–26 [Google Scholar]
  137. Yazawa M, Hsueh B, Jia X, Paşca AM, Bernstein JA. et al. 2011. Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 471:230–34 [Google Scholar]
  138. Ye W, Shimamura K, Rubenstein JL, Hynes MA, Rosenthal A. 1998. FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell 93:755–66 [Google Scholar]
  139. Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T. et al. 2011. MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 476:228–31 [Google Scholar]
  140. Yoshioka N, Gros E, Li H-R, Kumar S, Deacon DC. et al. 2013. Efficient generation of human iPSCs by a synthetic self-replicative RNA. Cell Stem Cell 13:246–54 [Google Scholar]
  141. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL. et al. 2007. Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–20 [Google Scholar]
  142. Zeng H, Shen EH, Hohmann JG, Oh SW, Bernard A. et al. 2012. Large-scale cellular-resolution gene profiling in human neocortex reveals species-specific molecular signatures. Cell 149:483–96 [Google Scholar]
  143. Zhang Y, Pak C, Han Y, Ahlenius H, Zhang Z. et al. 2013. Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron 78:785–98 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error