The fragile X mutation impairs homeostatic plasticity in human neurons by blocking synaptic retinoic acid signaling

Science Translational Medicine

Volumn 10, Issue 452, 2018, Pages

  Zhang, Zhenjie ^a   Marro, Samuele G ^a   Zhang, Yingsha ^a   Arendt, Kristin L ^a   Patzke, Christopher ^a   Zhou, Bo ^a   Fair, Tyler ^a   Yang, Nan ^a   Südhof, Thomas C ^a   Wernig, Marius ^a   Chen, Lu ^a  

^a STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FRAGILE X MENTAL RETARDATION PROTEIN; RETINOIC ACID;

ANIMAL CELL; ARTICLE; CONTROLLED STUDY; EMBRYO; EMBRYONIC STEM CELL; FMR1 GENE; FRAGILE X SYNDROME; GENE EXPRESSION; GENE INACTIVATION; GENE MUTATION; HUMAN; HUMAN CELL; INDUCED PLURIPOTENT STEM CELL; LOSS OF FUNCTION MUTATION; MOUSE; NERVE CELL CULTURE; NERVE CELL PLASTICITY; NONHUMAN; PRIORITY JOURNAL; SYNAPTIC TRANSMISSION; ALLELE; ANIMAL; CELL DIFFERENTIATION; CELL LINE; CYTOLOGY; DRUG EFFECT; EXCITATORY POSTSYNAPTIC POTENTIAL; GENETICS; HOMEOSTASIS; METABOLISM; MUTATION; NERVE CELL; NUCLEOTIDE SEQUENCE; PATHOPHYSIOLOGY; SIGNAL TRANSDUCTION; SYNAPSE; TRINUCLEOTIDE REPEAT; UPREGULATION;

ALLELES; ANIMALS; BASE SEQUENCE; CELL DIFFERENTIATION; CELL LINE; EMBRYONIC STEM CELLS; EXCITATORY POSTSYNAPTIC POTENTIALS; FRAGILE X MENTAL RETARDATION PROTEIN; FRAGILE X SYNDROME; HOMEOSTASIS; HUMANS; MICE; MUTATION; NEURONAL PLASTICITY; NEURONS; SIGNAL TRANSDUCTION; SYNAPSES; TRETINOIN; TRINUCLEOTIDE REPEATS; UP-REGULATION;

EID: 85050985156     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aar4338     Document Type: Article

References (95)

1. M. R. Santoro, S. M. Bray, S. T. Warren, Molecular mechanisms of fragile X syndrome: A twenty-year perspective. Annu. Rev. Pathol. 7, 219-245 (2012).
2. C. Bagni, F. Tassone, G. Neri, R. Hagerman, Fragile X syndrome: Causes, diagnosis, mechanisms, and therapeutics. J. Clin. Invest. 122, 4314-4322 (2012).
3. A. J. M. H. Verkerk, M. Pieretti, J. S. Sutcliffe, Y.-H. Fu, D. P. A. Kuhl, A. Pizzuti, O. Reiner, S. Richards, M. F. Victoria, F. Zhang, B. E. Eussen, G.-J. B. van Ommen, L. A. J. Blonden, G. J. Riggins, J. L. Chastain, C. B. Kunst, H. Galjaard, C. T. Caskey, D. L. Nelson, B. A. Oostra, S. T. Warren, Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905-914 (1991).
4. Y.-H. Fu, D. P. A. Kuhl, A. Pizzuti, M. Pieretti, J. S. Sutcliffe, S. Richards, A. J. M. H. Verkert, J. J. A. Holden, R. G. Fenwick Jr., S. T. Warren, B. A. Oostra, D. L. Nelson, C. T. Caskey, Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox. Cell 67, 1047-1058 (1991).
5. D. Heitz, D. Devys, G. Imbert, C. Kretz, J. L. Mandel, Inheritance of the fragile X syndrome: Size of the fragile X premutation is a major determinant of the transition to full mutation. J. Med. Genet. 29, 794-801 (1992).
6. J. A. Suhl, S. T. Warren, Single-nucleotide mutations in FMR1 reveal novel functions and regulatory mechanisms of the fragile X syndrome protein FMRP. J. Exp. Neurosci. 9, 35-41 (2015).
7. B. Laggerbauer, D. Ostareck, E.-M. Keidel, A. Ostareck-Lederer, U. Fischer, Evidence that fragile X mental retardation protein is a negative regulator of translation. Hum. Mol. Genet. 10, 329-338 (2001).
8. C. T. Ashley Jr., K. D. Wilkinson, D. Reines, S. T. Warren, FMR1 protein: Conserved RNP family domains and selective RNA binding. Science 262, 563-566 (1993).
9. H. L. Hinds, C. T. Ashley, J. S. Sutcliffe, D. L. Nelson, S. T. Warren, D. E. Housman, M. Schalling, Tissue specific expression of FMR-1 provides evidence for a functional role in fragile X syndrome. Nat. Genet. 3, 36-43 (1993).
10. L. Chen, S.-W. Yun, J. Seto, W. Liu, M. Toth, The fragile X mental retardation protein binds and regulates a novel class of mRNAs containing U rich target sequences. Neuroscience 120, 1005-1017 (2003).
11. K. Y. Miyashiro, A. Beckel-Mitchener, T. P. Purk, K. G. Becker, T. Barret, L. Liu, S. Carbonetto, I. J. Weiler, W. T. Greenough, J. Eberwine, RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice. Neuron 37, 417-431 (2003).
12. J. C. Darnell, S. J. Van Driesche, C. Zhang, K. Y. S. Hung, A. Mele, C. E. Fraser, E. F. Stone, C. Chen, J. J. Fak, S. W. Chi, D. D. Licatalosi, J. D. Richter, R. B. Darnell, FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247-261 (2011).
13. G. J. Bassell, S. T. Warren, Fragile X syndrome: Loss of local mRNA regulation alters synaptic development and function. Neuron 60, 201-214 (2008).
14. Z. Li, Y. Zhang, L. Ku, K. D. Wilkinson, S. T. Warren, Y. Fenga, The fragile X mental retardation protein inhibits translation via interacting with mRNA. Nucleic Acids Res. 29, 2276-2283 (2001).
15. J. R. Gibson, A. F. Bartley, S. A. Hays, K. M. Huber, Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of fragile X syndrome. J. Neurophysiol. 100, 2615-2626 (2008).
16. R. Tyzio, R. Nardou, D. C. Ferrari, T. Tsintsadze, A. Shahrokhi, S. Eftekhari, I. Khalilov, V. Tsintsadze, C. Brouchoud, G. Chazal, E. Lemonnier, N. Lozovaya, N. Burnashev, Y. Ben-Ari, Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science 343, 675-679 (2014).
17. D. Centonze, S. Rossi, V. Mercaldo, I. Napoli, M. T. Ciotti, V. De Chiara, A. Musella, C. Prosperetti, P. Calabresi, G. Bernardi, C. Bagni, Abnormal striatal GABA transmission in the mouse model for the fragile X syndrome. Biol. Psychiatry 63, 963-973 (2008).
18. G. Curia, T. Papouin, P. Séguéla, M. Avoli, Downregulation of tonic GABAergic inhibition in a mouse model of fragile X syndrome. Cereb. Cortex 19, 1515-1520 (2009).
19. J. L. Olmos-Serrano, S. M. Paluszkiewicz, B. S. Martin, W. E. Kaufmann, J. G. Corbin, M. M. Huntsman, Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome. J. Neurosci. 30, 9929-9938 (2010).
20. J. Larson, R. E. Jessen, D. Kim, A.-K. S. Fine, J. du Hoffmann, Age-dependent and selective impairment of long-term potentiation in the anterior piriform cortex of mice lacking the fragile X mental retardation protein. J. Neurosci. 25, 9460-9469 (2005).
21. J. Li, M. R. Pelletier, J.-L. Perez Velazquez, P. L. Carlen, Reduced cortical synaptic plasticity and GluR1 expression associated with fragile X mental retardation protein deficiency. Mol. Cell. Neurosci. 19, 138-151 (2002).
22. K. M. Huber, S. M. Gallagher, S. T. Warren, M. F. Bear, Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl. Acad. Sci. U.S.A. 99, 7746-7750 (2002).
23. S. Coghlan, J. Horder, B. Inkster, M. Andreina Mendez, D. G. Murphy, D. J. Nutt, GABA system dysfunction in autism and related disorders: From synapse to symptoms. Neurosci. Biobehav. Rev. 36, 2044-2055 (2012).
24. L. K. Fung, E.-M. Quintin, B. W. Haas, A. L. Reiss, Conceptualizing neurodevelopmental disorders through a mechanistic understanding of fragile X syndrome and Williams syndrome. Curr. Opin. Neurol. 25, 112-124 (2012).
25. S. M. Paluszkiewicz, B. S. Martin, M. M. Huntsman, Fragile X syndrome: The GABAergic system and circuit dysfunction. Dev. Neurosci. 33, 349-364 (2011).
26. T. Wang, S. M. Bray, S. T. Warren, New perspectives on the biology of fragile X syndrome. Curr. Opin. Genet. Dev. 22, 256-263 (2012).
27. A. Contractor, V. A. Klyachko, C. Portera-Cailliau, Altered neuronal and circuit excitability in fragile X syndrome. Neuron 87, 699-715 (2015).
28. B. E. Pfeiffer, K. M. Huber, The state of synapses in fragile X syndrome. Neuroscientist 15, 549-567 (2009).
29. F. Sarti, Z. Zhang, J. Schroeder, L. Chen, Rapid suppression of inhibitory synaptic transmission by retinoic acid. J. Neurosci. 33, 11440-11450 (2013).
30. M. E. Soden, L. Chen, Fragile X protein FMRP is required for homeostatic plasticity an d regulation of synaptic strength by retinoic acid. J. Neurosci. 30, 16910-16921 (2010).
31. G. Turrigiano, Homeostatic synaptic plasticity: Local and global mechanisms for stabilizing neuronal function. Cold Spring Harb. Perspect. Biol. 4, a005736 (2012).
32. G. G. Turrigiano, K. R. Leslie, N. S. Desai, L. C. Rutherford, S. B. Nelson, Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature 391, 892-896 (1998).
33. P. Chambon, A decade of molecular biology of retinoic acid receptors. FASEB J. 10, 940-954 (1996).
34. J. Aoto, C. I. Nam, M. M. Poon, P. Ting, L. Chen, Synaptic signaling by all-trans retinoic acid in homeostatic synaptic plasticity. Neuron 60, 308-320 (2008).
35. F. Sarti, J. Schroeder, J. Aoto, L. Chen, Conditional RAR knockout mice reveal acute requirement for retinoic acid and RAR? in homeostatic plasticity. Front. Mol. Neurosci. 5, 16 (2012).
36. M. M. Poon, L. Chen, Retinoic acid-gated sequence-specific translational control by RAR. Proc. Natl. Acad. Sci. U.S.A. 105, 20303-20308 (2008).
37. K. L. Arendt, Z. Zhang, S. Ganesan, M. Hintze, M. M. Shin, Y. Tang, A. Cho, I. A. Graef, L. Chen, Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis. Proc. Natl. Acad. Sci. U.S.A. 112, E5744-E5752 (2015).
38. H.-L. Wang, Z. Zhang, M. Hintze, L. Chen, Decrease in calcium concentration triggers neuronal retinoic acid synthesis during homeostatic synaptic plasticity. J. Neurosci. 31, 17764-17771 (2011).
39. B. Maghsoodi, M. M. Poon, C. I. Nam, J. Aoto, P. Ting, L. Chen, Retinoic acid regulates RAR-mediated control of translation in dendritic RNA granules during homeostatic synaptic plasticity. Proc. Natl. Acad. Sci. U.S.A. 105, 16015-16020 (2008).
40. J. H. Hanna, K. Saha, R. Jaenisch, Pluripotency and cellular reprogramming: Facts, hypotheses, unresolved issues. Cell 143, 508-525 (2010).
41. K. Okita, S. Yamanaka, Induced pluripotent stem cells: Opportunities and challenges. Philos. Trans. R. Soc. Lond. B Biol. Sci. 366, 2198-2207 (2011).
42. Y. Zhang, C. Pak, Y. Han, H. Ahlenius, Z. Zhang, S. Chanda, S. Marro, C. Patzke, C. Acuna, J. Covy, W. Xu, N. Yang, T. Danko, L. Chen, M. Wernig, T. C. Südhof, Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron 78, 785-798 (2013).
43. Z. P. Pang, N. Yang, T. Vierbuchen, A. Ostermeier, D. R. Fuentes, T. Q. Yang, A. Citri, V. Sebastiano, S. Marro, T. C. Südhof, M. Wernig, Induction of human neuronal cells by defined transcription factors. Nature 476, 220-223 (2011).
44. S. P. Pasca, G. Panagiotakos, R. E. Dolmetsch, Generating human neurons in vitro and using them to understand neuropsychiatric disease. Annu. Rev. Neurosci. 37, 479-501 (2014).
45. M. C. Marchetto, F. H. Gage, Modeling brain disease in a dish: Really? Cell Stem Cell 10, 642-645 (2012).
46. Y. Verlinsky, N. Strelchenko, V. Kukharenko, S. Rechitsky, O. Verlinsky, V. Galat, A. Kuliev, Human embryonic stem cell lines with genetic disorders. Reprod. Biomed. Online 10, 105-110 (2005).
47. R. Eiges, A. Urbach, M. Malcov, T. Frumkin, T. Schwartz, A. Amit, Y. Yaron, A. Eden, O. Yanuka, N. Benvenisty, D. Ben-Yosef, Developmental study of fragile X syndrome using human embryonic stem cells derived from preimplantation genetically diagnosed embryos. Cell Stem Cell 1, 568-577 (2007).
48. M. Avitzour, H. Mor-Shaked, S. Yanovsky-Dagan, S. Aharoni, G. Altarescu, P. Renbaum, T. Eldar-Geva, O. Schonberger, E. Levy-Lahad, S. Epsztejn-Litman, R. Eiges, FMR1 epigenetic silencing commonly occurs in undifferentiated fragile X-affected embryonic stem cells. Stem Cell Rep. 3, 699-706 (2014).
49. J. Gerhardt, M. J. Tomishima, N. Zaninovic, D. Colak, Z. Yan, Q. Zhan, Z. Rosenwaks, S. R. Jaffrey, C. L. Schildkraut, The DNA replication program is altered at the FMR1 locus in fragile X embryonic stem cells. Mol. Cell 53, 19-31 (2014).
50. O. Bar-Nur, I. Caspi, N. Benvenisty, Molecular analysis of FMR1 reactivation in fragile-X induced pluripotent stem cells and their neuronal derivatives. J. Mol. Cell Biol. 4, 180-183 (2012).
51. D. J. Brick, H. E. Nethercott, S. Montesano, M. G. Banuelos, A. E. Stover, S. S. Schutte, Diane K. O'Dowd, R. J. Hagerman, M. Ono, D. R. Hessl, F. Tassone, P. H. Schwartz, The autism spectrum disorders stem cell resource at children's hospital of orange county: Implications for disease modeling and drug discovery. Stem Cells Transl. Med. 3, 1275-1286 (2014).
52. C. E. F. de Esch, M. Ghazvini, F. Loos, N. Schelling-Kazaryan, W. Widagdo, S. T. Munshi, E. van der Wal, H. Douben, N. Gunhanlar, S. A. Kushner, W. W. M. P. Pijnappel, F. M. S. de Vrij, N. Geijsen, J. Gribnau, R. Willemsen, Epigenetic characterization of the FMR1 promoter in induced pluripotent stem cells from human fibroblasts carrying an unmethylated full mutation. Stem Cell Rep. 3, 548-555 (2014).
53. M. E. Doers, M. T. Musser, R. Nichol, E. R. Berndt, M. Baker, T. M. Gomez, S.-C. Zhang, L. Abbeduto, A. Bhattacharyya, iPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth. Stem Cells Dev. 23, 1777-1787 (2014).
54. T. Halevy, C. Czech, N. Benvenisty, Molecular mechanisms regulating the defects in fragile X syndrome neurons derived from human pluripotent stem cells. Stem Cell Rep. 4, 37-46 (2015).
55. S. D. Sheridan, K. M. Theriault, S. A. Reis, F. Zhou, J. M. Madison, L. Daheron, J. F. Loring, S. J. Haggarty, Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of fragile X syndrome. PLOS ONE 6, e26203 (2011).
56. A. Urbach, O. Bar-Nur, G. Q. Daley, N. Benvenisty, Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. Cell Stem Cell 6, 407-411 (2010).
57. M. Telias, M. Segal, D. Ben-Yosef, Neural differentiation of Fragile X human embryonic stem cells reveals abnormal patterns of development despite successful neurogenesis. Dev. Biol. 374, 32-45 (2013).
58. M. Niedringhaus, R. Dumitru, A. M. Mabb, Y. Wang, B. D. Philpot, N. L. Allbritton, A. M. Taylor, Transferable neuronal mini-cultures to accelerate screening in primary and induced pluripotent stem cell-derived neurons. Sci. Rep. 5, 8353 (2015).
59. M. Telias, L. Kuznitsov-Yanovsky, M. Segal, D. Ben-Yosef, Functional deficiencies in fragile X neurons derived from human embryonic stem cells. J. Neurosci. 35, 15295-15306 (2015).
60. S. M. Chambers, C. A. Fasano, E. P. Papapetrou, M. Tomishima, M. Sadelain, L. Studer, Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol. 27, 275-280 (2009).
61. The Hd iPSC Consortium, Induced pluripotent stem cells from patients with Huntington's disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell 11, 264-278 (2012).
62. F. Soldner, J. Laganière, A. W. Cheng, D. Hockemeyer, Q. Gao, R. Alagappan, V. Khurana, L. I. Golbe, R. H. Myers, S. Lindquist, L. Zhang, D. Guschin, L. K. Fong, B. J. Vu, X. Meng, F. D. Urnov, E. J. Rebar, P. D. Gregory, H. S. Zhang, R. Jaenisch, Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell 146, 318-331 (2011).
63. C. Patzke, Y. Han, J. Covy, F. Yi, S. Maxeiner, M. Wernig, T. C. Südhof, Analysis of conditional heterozygous STXBP1 mutations in human neurons. J. Clin. Invest. 125, 3560-3571 (2015).
64. C. Patzke, T. C. Südhof, The conditional KO approach: Cre/Lox technology in human neurons. Rare Dis. 4, e1131884 (2016).
65. E. T. Kavalali, The mechanisms and functions of spontaneous neurotransmitter release. Nat. Rev. Neurosci. 16, 5-16 (2015).
66. S. B. Nelson, G. G. Turrigiano, Synaptic depression: A key player in the cortical balancing act. Nat. Neurosci. 1, 539-541 (1998).
67. L. Chen, A. G. Lau, F. Sarti, Synaptic retinoic acid signaling and homeostatic synaptic plasticity. Neuropharmacology 78, 3-12 (2014).
68. M. Telias, M. Segal, D. Ben-Yosef, Immature responses to GABA in fragile X neurons derived from human embryonic stem cells. Front. Cell. Neurosci. 10, 121 (2016).
69. D. Colak, N. Zaninovic, M. S. Cohen, Z. Rosenwaks, W.-Y. Yang, J. Gerhardt, M. D. Disney, S. R. Jaffrey, Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome. Science 343, 1002-1005 (2014).
70. Y.-W. A. Huang, B. Zhou, M. Wernig, T. C. Südhof, ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and A secretion. Cell 168, 427-441.e21 (2017).
71. E. M. Ullian, K. S. Christopherson, B. A. Barres, Role for glia in synaptogenesis. Glia 47, 209-216 (2004).
72. G. Incorpora, G. Sorge, A. Sorge, L. Pavone, Epilepsy in fragile X syndrome. Brain Dev. 24, 766-769 (2002).
73. E. Berry-Kravis, Epilepsy in fragile X syndrome. Dev. Med. Child Neurol. 44, 724-728 (2002).
74. E. Berry-Kravis, M. Raspa, L. Loggin-Hester, E. Bishop, D. Holiday, D. B. Bailey, Seizures in fragile X syndrome: Characteristics and comorbid diagnoses. Am. J. Intellect. Dev. Disabil. 115, 461-472 (2010).
75. K. L. Arendt, Y. Zhang, S. Jurado, R. C. Malenka, T. C. Südhof, L. Chen, Retinoic acid and LTP recruit postsynaptic AMPA receptors using distinct SNARE-dependent mechanisms. Neuron 86, 442-456 (2015).
76. M. W. Waung, K. M. Huber, Protein translation in synaptic plasticity: mGluR-LTD, Fragile X. Curr. Opin. Neurobiol. 19, 319-326 (2009).
77. M. D. Muenter, H. O. Perry, J. Ludwig, Chronic vitamin A intoxication in adults. Hepatic, neurologic and dermatologic complications. Am. J. Med. 50, 129-136 (1971).
78. P. R. Hull, C. D'Arcy, Acne, depression, and suicide. Dermatol. Clin. 23, 665-674 (2005).
79. J. D. Bremner, P. McCaffery, The neurobiology of retinoic acid in affective disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 315-331 (2008).
80. J. M. Scher, Psychotic reaction to disulfiram. JAMA 201, 1051 (1967).
81. O. Martensen-Larsen, Psychotic phenomena provoked by tetra-ethylthiuram disulfide. Q. J. Stud. Alcohol 12, 206-216 (1951).
82. S. C. Liddon, R. Satran, Disulfiram (Antabuse) psychosis. Am. J. Psychiatry 123, 1284-1289 (1967).
83. D. L. Guris, G. Duester, V. E. Papaioannou, A. Imamoto, Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome. Dev. Cell 10, 81-92 (2006).
84. M. E. Ceylan, A. Turkcan, E. Mutlu, O. Onal, Manic episode with psychotic symptoms associated with high dose of disulfiram: A case report. J. Clin. Psychopharmacol. 27, 224-225 (2007).
85. A. X. Yee, Y.-T. Hsu, L. Chen, A metaplasticity view of the interaction between homeostatic and Hebbian plasticity. Philos. Trans. R. Soc. Lond. B Biol. Sci. 372, 20160155 (2017).
86. M.-Y. Chiang, D. Misner, G. Kempermann, T. Schikorski, V. Giguère, H. M. Sucov, F. H. Gage, C. F. Stevens, R. M. Evans, An essential role for retinoid receptors RAR? and RXR? in long-term potentiation and depression. Neuron 21, 1353-1361 (1998).
87. S. Cocco, G. Diaz, R. Stancampiano, A. Diana, M. Carta, R. Curreli, L. Sarais, F. Fadda, Vitamin A deficiency produces spatial learning and memory impairment in rats. Neuroscience 115, 475-482 (2002).
88. D. L. Misner, S. Jacobs, Y. Shimizu, A. M. de Urquiza, L. Solomin, T. Perlmann, L. M. De Luca, C. F. Stevens, R. M. Evans, Vitamin A deprivation results in reversible loss of hippocampal long-term synaptic plasticity. Proc. Natl. Acad. Sci. U.S.A. 98, 11714-11719 (2001).
89. M. Nomoto, Y. Takeda, S. Uchida, K. Mitsuda, H. Enomoto, K. Saito, T. Choi, A. M. Watabe, S. Kobayashi, S. Masushige, T. Manabe, S. Kida, Dysfunction of the RAR/RXR signaling pathway in the forebrain impairs hippocampal memory and synaptic plasticity. Mol. Brain 5, 8 (2012).
90. V. Sebastiano, M. L. Maeder, J. F. Angstman, B. Haddad, C. Khayter, D. T. Yeo, M. J. Goodwin, J. S. Hawkins, C. L. Ramirez, L. F. Z. Batista, S. E. Artandi, M. Wernig, J. K. Joung, In situ genetic correction of the sickle cell anemia mutation in human induced pluripotent stem cells using engineered zinc finger nucleases. Stem Cells 29, 1717-1726 (2011).
91. C. Xu, M. S. Inokuma, J. Denham, K. Golds, P. Kundu, J. D. Gold, M. K. Carpenter, Feeder-free growth of undifferentiated human embryonic stem cells. Nat. Biotechnol. 19, 971-974 (2001).
92. N. E. Sanjana, O. Shalem, F. Zhang, Improved vectors and genome-wide libraries for CRISPR screening. Nat. Methods 11, 783-784 (2014).
93. C.-Y. Park, T. Halevy, D. R. Lee, J. J. Sung, J. S. Lee, O. Yanuka, N. Benvenisty, D.-W. Kim, Reversion of FMR1 methylation and silencing by editing the triplet repeats in fragile X iPSC-derived neurons. Cell Rep. 13, 234-241 (2015).
94. C. Chen, H. Okayama, High-efficiency transformation of mammalian cells by plasmid DNA. Mol. Cell. Biol. 7, 2745-2752 (1987).
95. L. Lisowski, A. P. Dane, K. Chu, Y. Zhang, S. C. Cunningham, E. M. Wilson, S. Nygaard, M. Grompe, I. E. Alexander, M. A. Kay, Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature 506, 382-386 (2014).