(54.236.58.220) 您好!臺灣時間:2021/03/08 09:43
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果

詳目顯示:::

我願授權國圖
: 
twitterline
研究生:楊上知
研究生(外文):Shang-Chih Yang
論文名稱:利用RNA干擾技術在人類胚胎幹細胞建立高通量篩選並揭示ATF1基因在早期神經外胚層分化的新功能
論文名稱(外文):Establish an RNA interference based high-throughput screening in human embryonic stem cell and reveal a novel function of ATF1 in early neuroectoderm differentiation
指導教授:呂仁
指導教授(外文):Jean Lu
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2019
畢業學年度:107
語文別:英文
論文頁數:85
中文關鍵詞:早期發育高通量篩選掌管基因
外文關鍵詞:early developmenthigh-throughput screengatekeeper
相關次數:
  • 被引用被引用:0
  • 點閱點閱:30
  • 評分評分:系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔
  • 下載下載:6
  • 收藏至我的研究室書目清單書目收藏:0
藉由在人類胚胎幹細胞做shRNA高通量篩選,我發現了一個新穎的多潛能調控基因ATF1。在降低ATF1在人類胚胎幹細胞的表現量時,發現神經外胚層的標誌基因會增加,但內胚層、中胚層及滋養外胚層的標誌基因卻沒有改變。值得注意的是,無論是在維持自我更新或是促進神經外胚層分化的培養環境中使用短髮夹RNA (shRNA)、干擾RNA(siRNA)去減少ATF1在人類胚胎幹細胞的表現量或是利用CRISPR/Cas9基因編輯技術剃除ATF1基因都足以使SOX2和PAX6表現量上升。此外,若是在神經外胚層誘導的培養環境中過量表現ATF1則會壓制神經外胚層分化的程度。而內生性的ATF1表現量在外胚層誘導時,會在1-3天後以後自發地減少。藉由雙重抑制ATF1與SOX2表現量發現PAX6和SOX1表現量則會受到抑制。顯示ATF1經由SOX2來調控PAX6 和SOX1表現量。利用螢光素酶檢測系统則確認了ATF1能在SOX2基因表現的調控上作為一種抑制表現的調控因子。總結以上的實驗與發現,我發現了ATF1的新穎作用,而這些研究結果相信對人類胚胎幹細胞在極早期的神經外胚層分化的調控上能有更進一步的理解。
By a shRNA high-throughput screen, I reveal that Activating Transcription Factor 1 (ATF1) is a novel pluripotent regulator in human embryonic stem cells (hESCs). The knockdown of ATF1 expression significantly upregulated neuroectoderm genes but not mesoderm, endoderm, and trophectoderm genes. Of note, downregulation or knockout of ATF1 with shRNA, siRNA, or CRISPR/Cas9 was sufficient to upregulate SOX2 and PAX6 expression under the undifferentiated or differentiated conditions, while overexpression of ATF1 suppressed neuroectoderm differentiation. Endogenous ATF1 was spontaneously downregulated after day(s) 1-3 of neural induction. By double knockdown experiments, upregulation of SOX2 was critical for the increase of PAX6 and SOX1 expression in shATF1 hESCs. Using the luciferase reporter assay, ATF1 acted as a negative transcriptional regulator of SOX2 gene expression. In summary, the novel function of ATF1 was discovered and these findings contribute to a broader understanding of the very first steps of regulating neuroectoderm differentiation in hESCs.
Table of Contents
致謝……………………………………………………………………………….....i
Table of Contents…………………………………………………………….…..…ii
List of Figures………………………………………………………………….……vi
List of Tables..............................viii
List of Appendices……………………………………………………………………..ix
中文摘要…………………………………………………………………….……….x
Abstract………………………………………………...……………………………xi
Chapter 1. Introduction………………………………...………………………….1
1-1 Embryonic stem cells and induced pluripotent stem cells………………………..1
1-2 The pluripotent regulatory circuit in ESCs ………………………….………...…2
1-3 Gene expression signature analysis in pluripotent stem cells……………..........3
1-4 High-throughput functional assays in hESCs………………………………........5
1-5 The application of ESCs/iPSCs derived neuron cells……………………………6
1-6 The novel functions of ATF1 in hESCs………….……………………..…..........7
Chapter 2. Materials and Methods………………………..………………………9
2-1. Cell lines and culture conditions…..…………………………………9
2-2. A shRNA high-throughput screen………...………………………………..10
2-3. Plasmids ……………………………………………………………………….11
2-4. Lentivirus production and hESC infection………………………12
2-5. RNA extraction and quantitative Real-Time PCR (qRT-PCR)….…..12
2-6. Western blot analysis ……………………………………………………..13
2-7. Flow cytometry for cell cycle analysis …………….……...14
2-8. Immunofluorescence assays ………………………………………………….14
2-9. Knockout ATF1 by CRISPR/Cas9 technique ……………………….15
2-10. Differentiation of shRFP/shATF1-expressing hESCs into neurons................16
2-11. Electrophysiology studies …...……………………………………………….17
2-12. Mesoderm and endoderm differentiation …………………….18
2-13. Primitive streak-like cell differentiation……………..18
2-14.Chromatin immunoprecipitation (ChIP).…………………...….19
2-15.Luciferase reporter assays…………………………………………………….20
2-16.Statistical analysis.………………………………….……………………..21
Chapter 3. Results………………………………………………………..……….22
3-1. Identification of pluripotency-related genes by RNAi screening in hESCs.....22
3-2. Knockdown of ATF1 decreases alkaline phosphatase activity but not AB activity in hESCs…………………………………….24
3-3. Downregulation of ATF1 specifically induces hESCs toward neuroectoderm differentiation ……………………………….25
3-4. Excludes an off-target effect of shATF1 by siRNA, a rescue experiment, and CRISPR/Cas9 knockout assay……………26
3-5. A decrease in ATF1 accelerates the expression of hESC neuroectoderm markers SOX2, PAX6, and SOX1 in a neural differentiation condition…………………….27
3-6. ATF1-downregulated cells can differentiate into functional neurons …….28
3-7. The ATF1 expression level is downregulated upon entry into the early stage of neuroectoderm differentiation but maintained during differentiation into mesoderm, endoderm, and primitive streak cells ………29
3-8. Overexpression of ATF1 suppresses neuroectoderm differentiation of hESCs in neural differentiation condition ..……………………………………………..……..30
3-9. ATF1 binds to the SOX2 promoter and negatively regulates SOX2 promoter activity....31
3-10. ATF1 regulates the expression of PAX6 and SOX1 through SOX2...………...32
Chapter 4. Discussion………………………………………………………….……33
References……………………………………………………………………..…….39
Figures………………………………………………………………….………………..52
Tables…………………………………………………………………………..………76
Appendix ………………………………………………………………………………..82

List of Figures
Fig. 1. Strategy to identify critical regulators for hESC self-renewal by a functional shRNA screen ….…………….……..……...52
Fig. 2. Downregulation of ATF1 decreases the expression level of the hESC undifferentiated marker alkaline phosphatase (ALP) but not cell number (Almarblu, AB)………………………………………………..54
Fig. 3. Downregulation of ATF1 induces hESC neuroectoderm differentiation in undifferentiation medium …………......56
Fig. 4. To exclude the off-target effect of shATF1, SMARTpool si-ATF1, a rescue experiment, and CRISPR/Cas9 experiments were used to examine the expression of neuroectoderm genes……………58
Fig. 5. Downregulation of ATF1 upregulates the expression levels of neuroectoderm markers in shATF1 expressing HUES-6 cells ………60
Fig. 6. The decrease in ATF1 upregulates the expression of hESC neuroectoderm markers SOX2, PAX6, and SOX1 in neural differentiation condition ……...….62
Fig. 7. ATF1-downregulated cells can differentiate into functional neurons ………….…64
Fig.8. The expression levels of ATF1 are decreased during neural induction and maintained while hESCs differentiate into mesoderm, endoderm, or primitive streak…...........66
Fig. 9. Overexpression of ATF1 suppresses neuroectoderm differentiation…...…………68
Fig.10.Downregulation of ATF1 increases the expression levels of the hESC neuroectoderm markers SOX2, PAX6, and SOX1 in undifferentiation condition (Day1-3)…………………………………………………………………………………………70
Fig.11. ATF1 binds to the SOX2 promoter and acts as a negative regulator of SOX2 expression ……………………………………………………...72
Fig. 12. Downregulation of ATF1 and SOX2 decreases neuroectoderm gene expression..................74


List of Tables
Table 1. List of microarrays from different cell types or tissues........76
Table 2. Differentiated express gene list………………………….………..…77
Table 3. Lethal gene list ………………….......………..……………………………….78
Table 4. ALP downregulated list………………………………………………………79
Table 5. AB downregulated list…………………………………………………………80
Table 6. List of primer set used in real-time PCR………………………81

List of Appendices
Appendix1: Antibody for Western blot…………………………..……..……………..82
Appendix2: Antibody for Immunofluorescence assay ……………………..83
Appendix3: Table 1 References…………………………..……..……………….……..84
References

1. Hanna, J. H., Saha, K., and Jaenisch, R. (2010) Pluripotency and cellular reprogramming: facts, hypotheses, unresolved issues. Cell 143, 508-525
2. Jaenisch, R., and Young, R. (2008) Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 132, 567-582
3. Evans, M. J., and Kaufman, M. H. (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154-156
4. Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., and Jones, J. M. (1998) Embryonic stem cell lines derived from human blastocysts. Science 282, 1145-1147
5. Reubinoff, B. E., Pera, M. F., Fong, C. Y., Trounson, A., and Bongso, A. (2000) Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol 18, 399-404
6. Smith, K. P., Luong, M. X., and Stein, G. S. (2009) Pluripotency: toward a gold standard for human ES and iPS cells. J Cell Physiol 220, 21-29
7. Boyer, L. A., Lee, T. I., Cole, M. F., Johnstone, S. E., Levine, S. S., Zucker, J. P., Guenther, M. G., Kumar, R. M., Murray, H. L., Jenner, R. G., Gifford, D. K., Melton, D. A., Jaenisch, R., and Young, R. A. (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947-956
8. Loh, Y. H., Wu, Q., Chew, J. L., Vega, V. B., Zhang, W., Chen, X., Bourque, G., George, J., Leong, B., Liu, J., Wong, K. Y., Sung, K. W., Lee, C. W., Zhao, X. D., Chiu, K. P., Lipovich, L., Kuznetsov, V. A., Robson, P., Stanton, L. W., Wei, C. L., Ruan, Y., Lim, B., and Ng, H. H. (2006) The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38, 431-440
9. Takahashi, K., and Yamanaka, S. (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676
10. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861-872
11. Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., Nie, J., Jonsdottir, G. A., Ruotti, V., Stewart, R., Slukvin, II, and Thomson, J. A. (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920
12. Nakagawa, M., Koyanagi, M., Tanabe, K., Takahashi, K., Ichisaka, T., Aoi, T., Okita, K., Mochiduki, Y., Takizawa, N., and Yamanaka, S. (2008) Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26, 101-106
13. Tzatzalos, E., Abilez, O. J., Shukla, P., and Wu, J. C. (2016) Engineered heart tissues and induced pluripotent stem cells: Macro- and microstructures for disease modeling, drug screening, and translational studies. Adv Drug Deliv Rev 96, 234-244
14. Ebert, A. D., Liang, P., and Wu, J. C. (2012) Induced pluripotent stem cells as a disease modeling and drug screening platform. J Cardiovasc Pharmacol 60, 408-416
15. Rizzino, A., and Wuebben, E. L. (2016) Sox2/Oct4: A delicately balanced partnership in pluripotent stem cells and embryogenesis. Biochim Biophys Acta 1859, 780-791
16. Loh, K. M., and Lim, B. (2011) A precarious balance: pluripotency factors as lineage specifiers. Cell Stem Cell 8, 363-369
17. Thomson, M., Liu, S. J., Zou, L. N., Smith, Z., Meissner, A., and Ramanathan, S. (2011) Pluripotency factors in embryonic stem cells regulate differentiation into germ layers. Cell 145, 875-889
18. Wang, Z., Oron, E., Nelson, B., Razis, S., and Ivanova, N. (2012) Distinct lineage specification roles for NANOG, OCT4, and SOX2 in human embryonic stem cells. Cell Stem Cell 10, 440-454
19. Ring, K. L., Tong, L. M., Balestra, M. E., Javier, R., Andrews-Zwilling, Y., Li, G., Walker, D., Zhang, W. R., Kreitzer, A. C., and Huang, Y. (2012) Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell Stem Cell 11, 100-109
20. Lee, B. K., Shen, W., Lee, J., Rhee, C., Chung, H., Kim, K. Y., Park, I. H., and Kim, J. (2015) Tgif1 Counterbalances the Activity of Core Pluripotency Factors in Mouse Embryonic Stem Cells. Cell Rep 13, 52-60
21. Cole, M. F., Johnstone, S. E., Newman, J. J., Kagey, M. H., and Young, R. A. (2008) Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. Genes Dev 22, 746-755
22. Chitilian, J. M., Thillainadesan, G., Manias, J. L., Chang, W. Y., Walker, E., Isovic, M., Stanford, W. L., and Torchia, J. (2014) Critical components of the pluripotency network are targets for the p300/CBP interacting protein (p/CIP) in embryonic stem cells. Stem Cells 32, 204-215
23. Yu, H. B., Kunarso, G., Hong, F. H., and Stanton, L. W. (2009) Zfp206, Oct4, and Sox2 are integrated components of a transcriptional regulatory network in embryonic stem cells. J Biol Chem 284, 31327-31335
24. Zappone, M. V., Galli, R., Catena, R., Meani, N., De Biasi, S., Mattei, E., Tiveron, C., Vescovi, A. L., Lovell-Badge, R., Ottolenghi, S., and Nicolis, S. K. (2000) Sox2 regulatory sequences direct expression of a (beta)-geo transgene to telencephalic neural stem cells and precursors of the mouse embryo, revealing regionalization of gene expression in CNS stem cells. Development 127, 2367-2382
25. Ellis, P., Fagan, B. M., Magness, S. T., Hutton, S., Taranova, O., Hayashi, S., McMahon, A., Rao, M., and Pevny, L. (2004) SOX2, a persistent marker for multipotential neural stem cells derived from embryonic stem cells, the embryo or the adult. Dev Neurosci 26, 148-165
26. Avilion, A. A., Nicolis, S. K., Pevny, L. H., Perez, L., Vivian, N., and Lovell-Badge, R. (2003) Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 17, 126-140
27. Graham, V., Khudyakov, J., Ellis, P., and Pevny, L. (2003) SOX2 functions to maintain neural progenitor identity. Neuron 39, 749-765
28. Perez-Iratxeta, C., Palidwor, G., Porter, C. J., Sanche, N. A., Huska, M. R., Suomela, B. P., Muro, E. M., Krzyzanowski, P. M., Hughes, E., Campbell, P. A., Rudnicki, M. A., and Andrade, M. A. (2005) Study of stem cell function using microarray experiments. FEBS Lett 579, 1795-1801
29. Sato, N., Sanjuan, I. M., Heke, M., Uchida, M., Naef, F., and Brivanlou, A. H. (2003) Molecular signature of human embryonic stem cells and its comparison with the mouse. Dev Biol 260, 404-413
30. Ramalho-Santos, M., Yoon, S., Matsuzaki, Y., Mulligan, R. C., and Melton, D. A. (2002) "Stemness": transcriptional profiling of embryonic and adult stem cells. Science 298, 597-600
31. Assou, S., Le Carrour, T., Tondeur, S., Strom, S., Gabelle, A., Marty, S., Nadal, L., Pantesco, V., Reme, T., Hugnot, J. P., Gasca, S., Hovatta, O., Hamamah, S., Klein, B., and De Vos, J. (2007) A meta-analysis of human embryonic stem cells transcriptome integrated into a web-based expression atlas. Stem Cells 25, 961-973
32. Assou, S., Cerecedo, D., Tondeur, S., Pantesco, V., Hovatta, O., Klein, B., Hamamah, S., and De Vos, J. (2009) A gene expression signature shared by human mature oocytes and embryonic stem cells. BMC Genomics 10, 10
33. Chin, M. H., Mason, M. J., Xie, W., Volinia, S., Singer, M., Peterson, C., Ambartsumyan, G., Aimiuwu, O., Richter, L., Zhang, J., Khvorostov, I., Ott, V., Grunstein, M., Lavon, N., Benvenisty, N., Croce, C. M., Clark, A. T., Baxter, T., Pyle, A. D., Teitell, M. A., Pelegrini, M., Plath, K., and Lowry, W. E. (2009) Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 5, 111-123
34. Desbordes, S. C., Placantonakis, D. G., Ciro, A., Socci, N. D., Lee, G., Djaballah, H., and Studer, L. (2008) High-throughput screening assay for the identification of compounds regulating self-renewal and differentiation in human embryonic stem cells. Cell Stem Cell 2, 602-612
35. Xu, Y., Zhu, X., Hahm, H. S., Wei, W., Hao, E., Hayek, A., and Ding, S. Revealing a core signaling regulatory mechanism for pluripotent stem cell survival and self-renewal by small molecules. Proc Natl Acad Sci U S A 107, 8129-8134
36. Gonzalez, R., Jennings, L. L., Knuth, M., Orth, A. P., Klock, H. E., Ou, W., Feuerhelm, J., Hull, M. V., Koesema, E., Wang, Y., Zhang, J., Wu, C., Cho, C. Y., Su, A. I., Batalov, S., Chen, H., Johnson, K., Laffitte, B., Nguyen, D. G., Snyder, E. Y., Schultz, P. G., Harris, J. L., and Lesley, S. A. Screening the mammalian extracellular proteome for regulators of embryonic human stem cell pluripotency. Proc Natl Acad Sci U S A 107, 3552-3557
37. Chia, N. Y., Chan, Y. S., Feng, B., Lu, X., Orlov, Y. L., Moreau, D., Kumar, P., Yang, L., Jiang, J., Lau, M. S., Huss, M., Soh, B. S., Kraus, P., Li, P., Lufkin, T., Lim, B., Clarke, N. D., Bard, F., and Ng, H. H. A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity. Nature 468, 316-320
38. Chia, N. Y., Chan, Y. S., Feng, B., Lu, X., Orlov, Y. L., Moreau, D., Kumar, P., Yang, L., Jiang, J., Lau, M. S., Huss, M., Soh, B. S., Kraus, P., Li, P., Lufkin, T., Lim, B., Clarke, N. D., Bard, F., and Ng, H. H. (2010) A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity. Nature 468, 316-320
39. Xu, Y., Zhu, X., Hahm, H. S., Wei, W., Hao, E., Hayek, A., and Ding, S. (2010) Revealing a core signaling regulatory mechanism for pluripotent stem cell survival and self-renewal by small molecules. Proc Natl Acad Sci U S A 107, 8129-8134
40. Gonzalez, R., Jennings, L. L., Knuth, M., Orth, A. P., Klock, H. E., Ou, W., Feuerhelm, J., Hull, M. V., Koesema, E., Wang, Y., Zhang, J., Wu, C., Cho, C. Y., Su, A. I., Batalov, S., Chen, H., Johnson, K., Laffitte, B., Nguyen, D. G., Snyder, E. Y., Schultz, P. G., Harris, J. L., and Lesley, S. A. (2010) Screening the mammalian extracellular proteome for regulators of embryonic human stem cell pluripotency. Proc Natl Acad Sci U S A 107, 3552-3557
41. Poon, A., Zhang, Y., Chandrasekaran, A., Phanthong, P., Schmid, B., Nielsen, T. T., and Freude, K. K. (2017) Modeling neurodegenerative diseases with patient-derived induced pluripotent cells: Possibilities and challenges. N Biotechnol 39, 190-198
42. Nagoshi, N., and Okano, H. (2018) iPSC-derived neural precursor cells: potential for cell transplantation therapy in spinal cord injury. Cell Mol Life Sci 75, 989-1000
43. Yagi, T., Ito, D., Okada, Y., Akamatsu, W., Nihei, Y., Yoshizaki, T., Yamanaka, S., Okano, H., and Suzuki, N. (2011) Modeling familial Alzheimer's disease with induced pluripotent stem cells. Hum Mol Genet 20, 4530-4539
44. Kondo, T., Asai, M., Tsukita, K., Kutoku, Y., Ohsawa, Y., Sunada, Y., Imamura, K., Egawa, N., Yahata, N., Okita, K., Takahashi, K., Asaka, I., Aoi, T., Watanabe, A., Watanabe, K., Kadoya, C., Nakano, R., Watanabe, D., Maruyama, K., Hori, O., Hibino, S., Choshi, T., Nakahata, T., Hioki, H., Kaneko, T., Naitoh, M., Yoshikawa, K., Yamawaki, S., Suzuki, S., Hata, R., Ueno, S., Seki, T., Kobayashi, K., Toda, T., Murakami, K., Irie, K., Klein, W. L., Mori, H., Asada, T., Takahashi, R., Iwata, N., Yamanaka, S., and Inoue, H. (2013) Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell 12, 487-496
45. Oh, C. K., Sultan, A., Platzer, J., Dolatabadi, N., Soldner, F., McClatchy, D. B., Diedrich, J. K., Yates, J. R., 3rd, Ambasudhan, R., Nakamura, T., Jaenisch, R., and Lipton, S. A. (2017) S-Nitrosylation of PINK1 Attenuates PINK1/Parkin-Dependent Mitophagy in hiPSC-Based Parkinson's Disease Models. Cell Rep 21, 2171-2182
46. Heman-Ackah, S. M., Manzano, R., Hoozemans, J. J. M., Scheper, W., Flynn, R., Haerty, W., Cowley, S. A., Bassett, A. R., and Wood, M. J. A. (2017) Alpha-synuclein induces the unfolded protein response in Parkinson's disease SNCA triplication iPSC-derived neurons. Hum Mol Genet 26, 4441-4450
47. Madill, M., McDonagh, K., Ma, J., Vajda, A., McLoughlin, P., O'Brien, T., Hardiman, O., and Shen, S. (2017) Amyotrophic lateral sclerosis patient iPSC-derived astrocytes impair autophagy via non-cell autonomous mechanisms. Mol Brain 10, 22
48. Sun, X., Song, J., Huang, H., Chen, H., and Qian, K. (2018) Modeling hallmark pathology using motor neurons derived from the family and sporadic amyotrophic lateral sclerosis patient-specific iPS cells. Stem Cell Res Ther 9, 315
49. Zhang, N., Bailus, B. J., Ring, K. L., and Ellerby, L. M. (2016) iPSC-based drug screening for Huntington's disease. Brain Res 1638, 42-56
50. Xu, X., Tay, Y., Sim, B., Yoon, S. I., Huang, Y., Ooi, J., Utami, K. H., Ziaei, A., Ng, B., Radulescu, C., Low, D., Ng, A. Y. J., Loh, M., Venkatesh, B., Ginhoux, F., Augustine, G. J., and Pouladi, M. A. (2017) Reversal of Phenotypic Abnormalities by CRISPR/Cas9-Mediated Gene Correction in Huntington Disease Patient-Derived Induced Pluripotent Stem Cells. Stem Cell Reports 8, 619-633
51. Bordoni, M., Rey, F., Fantini, V., Pansarasa, O., Di Giulio, A. M., Carelli, S., and Cereda, C. (2018) From Neuronal Differentiation of iPSCs to 3D Neuro-Organoids: Modelling and Therapy of Neurodegenerative Diseases. Int J Mol Sci 19
52. Korhonen, P., Malm, T., and White, A. R. (2018) 3D human brain cell models: New frontiers in disease understanding and drug discovery for neurodegenerative diseases. Neurochem Int 120, 191-199
53. Centeno, E. G. Z., Cimarosti, H., and Bithell, A. (2018) 2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling. Mol Neurodegener 13, 27
54. Chen, M., Lee, H. K., Moo, L., Hanlon, E., Stein, T., and Xia, W. (2018) Common proteomic profiles of induced pluripotent stem cell-derived three-dimensional neurons and brain tissue from Alzheimer patients. J Proteomics 182, 21-33
55. Bolognin, S., Fossepre, M., Qing, X., Jarazo, J., Scancar, J., Moreno, E. L., Nickels, S. L., Wasner, K., Ouzren, N., Walter, J., Grunewald, A., Glaab, E., Salamanca, L., Fleming, R. M. T., Antony, P. M. A., and Schwamborn, J. C. (2019) 3D Cultures of Parkinson's Disease-Specific Dopaminergic Neurons for High Content Phenotyping and Drug Testing. Adv Sci (Weinh) 6, 1800927
56. Osaki, T., Uzel, S. G. M., and Kamm, R. D. (2018) Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons. Sci Adv 4, eaat5847
57. Hu, B. Y., Weick, J. P., Yu, J., Ma, L. X., Zhang, X. Q., Thomson, J. A., and Zhang, S. C. (2010) Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc Natl Acad Sci U S A 107, 4335-4340
58. Miranda, C. C., Fernandes, T. G., Pinto, S. N., Prieto, M., Diogo, M. M., and Cabral, J. M. S. (2018) A scale out approach towards neural induction of human induced pluripotent stem cells for neurodevelopmental toxicity studies. Toxicol Lett 294, 51-60
59. Llonch, S., Carido, M., and Ader, M. (2018) Organoid technology for retinal repair. Dev Biol 433, 132-143
60. Takahashi, J. (2017) Strategies for bringing stem cell-derived dopamine neurons to the clinic: The Kyoto trial. Prog Brain Res 230, 213-226
61. Studer, L. (2017) Strategies for bringing stem cell-derived dopamine neurons to the clinic-The NYSTEM trial. Prog Brain Res 230, 191-212
62. Kirkeby, A., Parmar, M., and Barker, R. A. (2017) Strategies for bringing stem cell-derived dopamine neurons to the clinic: A European approach (STEM-PD). Prog Brain Res 230, 165-190
63. Jin, X. L., and O'Neill, C. (2014) The regulation of the expression and activation of the essential ATF1 transcription factor in the mouse preimplantation embryo. Reproduction 148, 147-157
64. Bleckmann, S. C., Blendy, J. A., Rudolph, D., Monaghan, A. P., Schmid, W., and Schutz, G. (2002) Activating transcription factor 1 and CREB are important for cell survival during early mouse development. Mol Cell Biol 22, 1919-1925
65. Cowan, C. A., Klimanskaya, I., McMahon, J., Atienza, J., Witmyer, J., Zucker, J. P., Wang, S., Morton, C. C., McMahon, A. P., Powers, D., and Melton, D. A. (2004) Derivation of embryonic stem-cell lines from human blastocysts. N Engl J Med 350, 1353-1356
66. Yang, X., Hao, H., Xia, Z., Xu, G., Cao, Z., Chen, X., Liu, S., and Zhu, Y. (2016) Soluble IL-6 Receptor and IL-27 Subunit p28 Protein Complex Mediate the Antiviral Response through the Type III IFN Pathway. J Immunol 197, 2369-2381
67. Hailemariam, K., Iwasaki, K., Huang, B. W., Sakamoto, K., and Tsuji, Y. (2010) Transcriptional regulation of ferritin and antioxidant genes by HIPK2 under genotoxic stress. J Cell Sci 123, 3863-3871
68. Chou, Y. T., Lee, C. C., Hsiao, S. H., Lin, S. E., Lin, S. C., Chung, C. H., Chung, C. H., Kao, Y. R., Wang, Y. H., Chen, C. T., Wei, Y. H., and Wu, C. W. (2013) The emerging role of SOX2 in cell proliferation and survival and its crosstalk with oncogenic signaling in lung cancer. Stem Cells 31, 2607-2619
69. Wang, C. H., Ma, N., Lin, Y. T., Wu, C. C., Hsiao, M., Lu, F. L., Yu, C. C., Chen, S. Y., and Lu, J. (2012) A shRNA functional screen reveals Nme6 and Nme7 are crucial for embryonic stem cell renewal. Stem Cells 30, 2199-2211
70. Wen, Z., Nguyen, H. N., Guo, Z., Lalli, M. A., Wang, X., Su, Y., Kim, N. S., Yoon, K. J., Shin, J., Zhang, C., Makri, G., Nauen, D., Yu, H., Guzman, E., Chiang, C. H., Yoritomo, N., Kaibuchi, K., Zou, J., Christian, K. M., Cheng, L., Ross, C. A., Margolis, R. L., Chen, G., Kosik, K. S., Song, H., and Ming, G. L. (2014) Synaptic dysregulation in a human iPS cell model of mental disorders. Nature 515, 414-418
71. Lippmann, E. S., Estevez-Silva, M. C., and Ashton, R. S. (2014) Defined human pluripotent stem cell culture enables highly efficient neuroepithelium derivation without small molecule inhibitors. Stem Cells 32, 1032-1042
72. Sierra, R. A., Hoverter, N. P., Ramirez, R. N., Vuong, L. M., Mortazavi, A., Merrill, B. J., Waterman, M. L., and Donovan, P. J. (2018) TCF7L1 suppresses primitive streak gene expression to support human embryonic stem cell pluripotency. Development 145
73. Mignone, J. L., Kreutziger, K. L., Paige, S. L., and Murry, C. E. (2010) Cardiogenesis from human embryonic stem cells. Circ J 74, 2517-2526
74. Houlard, M., Berlivet, S., Probst, A. V., Quivy, J. P., Hery, P., Almouzni, G., and Gerard, M. (2006) CAF-1 is essential for heterochromatin organization in pluripotent embryonic cells. PLoS Genet 2, e181
75. Blum, B., Bar-Nur, O., Golan-Lev, T., and Benvenisty, N. (2009) The anti-apoptotic gene survivin contributes to teratoma formation by human embryonic stem cells. Nat Biotechnol 27, 281-287
76. Desmarais, J. A., Hoffmann, M. J., Bingham, G., Gagou, M. E., Meuth, M., and Andrews, P. W. (2012) Human embryonic stem cells fail to activate CHK1 and commit to apoptosis in response to DNA replication stress. Stem Cells 30, 1385-1393
77. Wang, Y., and Prywes, R. (2000) Activation of the c-fos enhancer by the erk MAP kinase pathway through two sequence elements: the c-fos AP-1 and p62TCF sites. Oncogene 19, 1379-1385
78. Gupta, P., and Prywes, R. (2002) ATF1 phosphorylation by the ERK MAPK pathway is required for epidermal growth factor-induced c-jun expression. J Biol Chem 277, 50550-50556
79. Zhang, X., Odom, D. T., Koo, S. H., Conkright, M. D., Canettieri, G., Best, J., Chen, H., Jenner, R., Herbolsheimer, E., Jacobsen, E., Kadam, S., Ecker, J. R., Emerson, B., Hogenesch, J. B., Unterman, T., Young, R. A., and Montminy, M. (2005) Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues. Proc Natl Acad Sci U S A 102, 4459-4464
80. Impey, S., McCorkle, S. R., Cha-Molstad, H., Dwyer, J. M., Yochum, G. S., Boss, J. M., McWeeney, S., Dunn, J. J., Mandel, G., and Goodman, R. H. (2004) Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell 119, 1041-1054
81. Zhou, J., Su, P., Li, D., Tsang, S., Duan, E., and Wang, F. (2010) High-efficiency induction of neural conversion in human ESCs and human induced pluripotent stem cells with a single chemical inhibitor of transforming growth factor beta superfamily receptors. Stem Cells 28, 1741-1750
82. Jang, J., Wang, Y., Lalli, M. A., Guzman, E., Godshalk, S. E., Zhou, H., and Kosik, K. S. (2016) Primary Cilium-Autophagy-Nrf2 (PAN) Axis Activation Commits Human Embryonic Stem Cells to a Neuroectoderm Fate. Cell 165, 410-420
83. Lin, Y. P., Ouchi, Y., Satoh, S., and Watanabe, S. (2009) Sox2 plays a role in the induction of amacrine and Muller glial cells in mouse retinal progenitor cells. Invest Ophthalmol Vis Sci 50, 68-74
84. Wen, J., Hu, Q., Li, M., Wang, S., Zhang, L., Chen, Y., and Li, L. (2008) Pax6 directly modulate Sox2 expression in the neural progenitor cells. Neuroreport 19, 413-417
85. Aota, S., Nakajima, N., Sakamoto, R., Watanabe, S., Ibaraki, N., and Okazaki, K. (2003) Pax6 autoregulation mediated by direct interaction of Pax6 protein with the head surface ectoderm-specific enhancer of the mouse Pax6 gene. Dev Biol 257, 1-13
86. Zhang, S., and Cui, W. (2014) Sox2, a key factor in the regulation of pluripotency and neural differentiation. World J Stem Cells 6, 305-311
87. Zhang, X., Huang, C. T., Chen, J., Pankratz, M. T., Xi, J., Li, J., Yang, Y., Lavaute, T. M., Li, X. J., Ayala, M., Bondarenko, G. I., Du, Z. W., Jin, Y., Golos, T. G., and Zhang, S. C. (2010) Pax6 is a human neuroectoderm cell fate determinant. Cell Stem Cell 7, 90-100
88. Du, Z. W., Ma, L. X., Phillips, C., and Zhang, S. C. (2013) miR-200 and miR-96 families repress neural induction from human embryonic stem cells. Development 140, 2611-2618
89. Hou, P. S., Chuang, C. Y., Kao, C. F., Chou, S. J., Stone, L., Ho, H. N., Chien, C. L., and Kuo, H. C. (2013) LHX2 regulates the neural differentiation of human embryonic stem cells via transcriptional modulation of PAX6 and CER1. Nucleic Acids Res 41, 7753-7770
90. Aloia, L., Di Stefano, B., Sessa, A., Morey, L., Santanach, A., Gutierrez, A., Cozzuto, L., Benitah, S. A., Graf, T., Broccoli, V., and Di Croce, L. (2014) Zrf1 is required to establish and maintain neural progenitor identity. Genes Dev 28, 182-197
91. Li, L., Nakaya, N., Chavali, V. R., Ma, Z., Jiao, X., Sieving, P. A., Riazuddin, S., Tomarev, S. I., Ayyagari, R., Riazuddin, S. A., and Hejtmancik, J. F. (2010) A mutation in ZNF513, a putative regulator of photoreceptor development, causes autosomal-recessive retinitis pigmentosa. Am J Hum Genet 87, 400-409
92. Liao, B. Y., and Zhang, J. (2008) Null mutations in human and mouse orthologs frequently result in different phenotypes. Proc Natl Acad Sci U S A 105, 6987-6992
93. Berger, R. P., Sun, Y. H., Kulik, M., Lee, J. K., Nairn, A. V., Moremen, K. W., Pierce, M., and Dalton, S. (2016) ST8SIA4-Dependent Polysialylation is Part of a Developmental Program Required for Germ Layer Formation from Human Pluripotent Stem Cells. Stem Cells 34, 1742-1752
94. Shen, J., and Walsh, C. A. (2005) Targeted disruption of Tgif, the mouse ortholog of a human holoprosencephaly gene, does not result in holoprosencephaly in mice. Mol Cell Biol 25, 3639-3647
95. Li, K., Turner, A. N., Chen, M., Brosius, S. N., Schoeb, T. R., Messiaen, L. M., Bedwell, D. M., Zinn, K. R., Anastasaki, C., Gutmann, D. H., Korf, B. R., and Kesterson, R. A. (2016) Mice with missense and nonsense NF1 mutations display divergent phenotypes compared with human neurofibromatosis type I. Dis Model Mech 9, 759-767
96. Peters, O. M., Cabrera, G. T., Tran, H., Gendron, T. F., McKeon, J. E., Metterville, J., Weiss, A., Wightman, N., Salameh, J., Kim, J., Sun, H., Boylan, K. B., Dickson, D., Kennedy, Z., Lin, Z., Zhang, Y. J., Daughrity, L., Jung, C., Gao, F. B., Sapp, P. C., Horvitz, H. R., Bosco, D. A., Brown, S. P., de Jong, P., Petrucelli, L., Mueller, C., and Brown, R. H., Jr. (2015) Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice. Neuron 88, 902-909
97. Shimomura, A., Okamoto, Y., Hirata, Y., Kobayashi, M., Kawakami, K., Kiuchi, K., Wakabayashi, T., and Hagiwara, M. (1998) Dominant negative ATF1 blocks cyclic AMP-induced neurite outgrowth in PC12D cells. J Neurochem 70, 1029-1034
98. Wei, W., Lu, Y., Hao, B., Zhang, K., Wang, Q., Miller, A. L., Zhang, L. R., Zhang, L. H., and Yue, J. (2015) CD38 Is Required for Neural Differentiation of Mouse Embryonic Stem Cells by Modulating Reactive Oxygen Species. Stem Cells 33, 2664-2673
99. Hsueh, Y. P., and Lai, M. Z. (1995) Overexpression of activation transcriptional factor 1 in lymphomas and in activated lymphocytes. J Immunol 154, 5675-5683
100. Jean, D., Tellez, C., Huang, S., Davis, D. W., Bruns, C. J., McConkey, D. J., Hinrichs, S. H., and Bar-Eli, M. (2000) Inhibition of tumor growth and metastasis of human melanoma by intracellular anti-ATF-1 single chain Fv fragment. Oncogene 19, 2721-2730
101. Brown, A. D., Lopez-Terrada, D., Denny, C., and Lee, K. A. (1995) Promoters containing ATF-binding sites are de-regulated in cells that express the EWS/ATF1 oncogene. Oncogene 10, 1749-1756
102. Atlas, E., Stramwasser, M., and Mueller, C. R. (2001) A CREB site in the BRCA1 proximal promoter acts as a constitutive transcriptional element. Oncogene 20, 7110-7114
103. Belmonte, N., Phillips, B. W., Massiera, F., Villageois, P., Wdziekonski, B., Saint-Marc, P., Nichols, J., Aubert, J., Saeki, K., Yuo, A., Narumiya, S., Ailhaud, G., and Dani, C. (2001) Activation of extracellular signal-regulated kinases and CREB/ATF-1 mediate the expression of CCAAT/enhancer binding proteins beta and -delta in preadipocytes. Mol Endocrinol 15, 2037-2049
104. Kingsley-Kallesen, M. L., Kelly, D., and Rizzino, A. (1999) Transcriptional regulation of the transforming growth factor-beta2 promoter by cAMP-responsive element-binding protein (CREB) and activating transcription factor-1 (ATF-1) is modulated by protein kinases and the coactivators p300 and CREB-binding protein. J Biol Chem 274, 34020-34028
105. Rolli, M., Kotlyarov, A., Sakamoto, K. M., Gaestel, M., and Neininger, A. (1999) Stress-induced stimulation of early growth response gene-1 by p38/stress-activated protein kinase 2 is mediated by a cAMP-responsive promoter element in a MAPKAP kinase 2-independent manner. J Biol Chem 274, 19559-19564
106. Zaman, K., Ryu, H., Hall, D., O'Donovan, K., Lin, K. I., Miller, M. P., Marquis, J. C., Baraban, J. M., Semenza, G. L., and Ratan, R. R. (1999) Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, p21(waf1/cip1), and erythropoietin. J Neurosci 19, 9821-9830
107. Zhang, J. W., Klemm, D. J., Vinson, C., and Lane, M. D. (2004) Role of CREB in transcriptional regulation of CCAAT/enhancer-binding protein beta gene during adipogenesis. J Biol Chem 279, 4471-4478
108. Lee, M. G., and Pedersen, P. L. (2003) Glucose metabolism in cancer: importance of transcription factor-DNA interactions within a short segment of the proximal region og the type II hexokinase promoter. J Biol Chem 278, 41047-41058
109. Iwasaki, K., Hailemariam, K., and Tsuji, Y. (2007) PIAS3 interacts with ATF1 and regulates the human ferritin H gene through an antioxidant-responsive element. J Biol Chem 282, 22335-22343
110. Okuyama, Y., Sowa, Y., Fujita, T., Mizuno, T., Nomura, H., Nikaido, T., Endo, T., and Sakai, T. (1996) ATF site of human RB gene promoter is a responsive element of myogenic differentiation. FEBS Lett 397, 219-224
111. Dong, Y., Asch, H. L., Ying, A., and Asch, B. B. (2002) Molecular mechanism of transcriptional repression of gelsolin in human breast cancer cells. Exp Cell Res 276, 328-336
112. Salnikow, K., Wang, S., and Costa, M. (1997) Induction of activating transcription factor 1 by nickel and its role as a negative regulator of thrombospondin I gene expression. Cancer Res 57, 5060-5066
113. Otani, T., Marchetto, M. C., Gage, F. H., Simons, B. D., and Livesey, F. J. (2016) 2D and 3D Stem Cell Models of Primate Cortical Development Identify Species-Specific Differences in Progenitor Behavior Contributing to Brain Size. Cell Stem Cell 18, 467-480
114. Ryan, S. J., Ehrlich, D. E., and Rainnie, D. G. (2016) Morphology and dendritic maturation of developing principal neurons in the rat basolateral amygdala. Brain Struct Funct 221, 839-854
115. Okaty, B. W., Miller, M. N., Sugino, K., Hempel, C. M., and Nelson, S. B. (2009) Transcriptional and electrophysiological maturation of neocortical fast-spiking GABAergic interneurons. J Neurosci 29, 7040-7052
116. Tripathy, S. J., Burton, S. D., Geramita, M., Gerkin, R. C., and Urban, N. N. (2015) Brain-wide analysis of electrophysiological diversity yields novel categorization of mammalian neuron types. J Neurophysiol 113, 3474-3489
117. Foldy, C., Darmanis, S., Aoto, J., Malenka, R. C., Quake, S. R., and Sudhof, T. C. (2016) Single-cell RNAseq reveals cell adhesion molecule profiles in electrophysiologically defined neurons. Proc Natl Acad Sci U S A 113, E5222-5231
118. Tripathy, S. J., Toker, L., Li, B., Crichlow, C. L., Tebaykin, D., Mancarci, B. O., and Pavlidis, P. (2017) Transcriptomic correlates of neuron electrophysiological diversity. PLoS Comput Biol 13, e1005814
119. Sasai, Y. (2013) Cytosystems dynamics in self-organization of tissue architecture. Nature 493, 318-326
120. Lancaster, M. A., Renner, M., Martin, C. A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P., and Knoblich, J. A. (2013) Cerebral organoids model human brain development and microcephaly. Nature 501, 373-379
121. Lancaster, M. A., and Knoblich, J. A. (2014) Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc 9, 2329-2340
122. Jo, J., Xiao, Y., Sun, A. X., Cukuroglu, E., Tran, H. D., Goke, J., Tan, Z. Y., Saw, T. Y., Tan, C. P., Lokman, H., Lee, Y., Kim, D., Ko, H. S., Kim, S. O., Park, J. H., Cho, N. J., Hyde, T. M., Kleinman, J. E., Shin, J. H., Weinberger, D. R., Tan, E. K., Je, H. S., and Ng, H. H. (2016) Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons. Cell Stem Cell 19, 248-257
連結至畢業學校之論文網頁點我開啟連結
註: 此連結為研究生畢業學校所提供,不一定有電子全文可供下載,若連結有誤,請點選上方之〝勘誤回報〞功能,我們會盡快修正,謝謝!
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關論文
 
無相關期刊
 
無相關點閱論文
 
系統版面圖檔 系統版面圖檔