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研究生：	包秉潔 Pao, Ping-Chieh
論文名稱：	探討新穎腦指蛋白(Brain Finger Protein), ZNF179, 參與神經元分化之作用 Investigation of the functional role of a novel brain finger protein, Znf179, in neuronal differentiation
指導教授：	張文昌 Chang, Wen-Chang
共同指導教授:	林鼎晏 Lin, Ding-Yen
學位類別：	博士 Doctor
系所名稱：	生物科學與科技學院 - 生物資訊與訊息傳遞研究所 Insitute of Bioinformatics and Biosignal Transduction
論文出版年：	2014
畢業學年度：	102
語文別：	英文
論文頁數：	81
中文關鍵詞：	Znf179 、神經分化、p27 、p35
外文關鍵詞：	Znf179, neuronal differentiation, p27, p35
相關次數：	點閱：130 下載：2
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於神經分化的過程中，分化中的細胞必須做出是要離開細胞週期抑或面對死亡的決定。神經分化刺激細胞產生許多改變，如分化相關基因的表達、細胞骨架的重組，以及細胞週期的停滯。細胞週期若是在分化中細胞持續運轉，會啟動與細胞週期相關的細胞死亡，將未離開細胞週期的細胞，或稱之為未準備好分化的細胞移除。研究指出，腦指蛋白Znf179主要表達在腦部，並且其表達量於胚胎發育之過程中逐漸上升，顯示Znf179對於神經系統發育的重要性。本研究中，我們發現Znf179的表現量隨著P19細胞神經分化的過程而上升。利用干擾性核醣核酸抑制Znf179的表達，明顯阻礙P19細胞以及初代培養小腦顆粒細胞之神經分化。藉由微陣列以及基因功能的分析，我們發現會隨Znf179表現抑制而改變其表達量的基因群，其功能主要與發育、細胞增生以及細胞週期調控相關。因此我們使用流式細胞儀觀察Znf179對於細胞週期的影響。首先，Znf179表達抑制會造成細胞週期無法停滯，而不利於神經分化，相同的現象也於溴化去氧尿苷標定實驗中所見。此外，兩個與細胞週期調控相關的分子於Znf179表達抑制時產生明顯改變。抑制Znf179表達會造成CDK5的活化蛋白p35表現量下降與細胞週期抑制蛋白p27蛋白量減少。顯示在神經分化過程中，Znf179表達上升藉著透過影響p35基因表現與p27蛋白質堆積，造成細胞週期停滯以利推動神經分化。

Leave or die, is a serious task for differentiating cells. During neuronal differentiation, cells need to be well-equipped for differentiation process. Gene expressions and cytoskeleton reorganizations are necessary for neuronal differentiation, but most important thing is to depart form cell cycle at the right time. Fail to exit cell cycle in time fires cell cycle-related neuronal death, eliminating cells which are not ready for neuronal differentiation. Brain finger protein, Znf179 was known to express predominantly in brain, and the expression significantly increased during embryogenesis, suggesting the potential role of Znf179 in neuronal development. In this study, we demonstrated that Znf179 expression increased gradually during P19 cells neuronal differentiation. Inhibition of Znf179 expression by RNA interference dramatically suppressed the neuronal differentiation of both P19 and primary cerebellar granular cells. By using microarray technique and functional annotation analysis, we identified the differentially expressed genes in Znf179-knockdown cells, and found that those genes were mostly involved in development, cell proliferation and cell cycle regulation. In our results, cell cycle arrest for neuronal differentiation was abolished in Znf179-knockdown cells. First, flow cytometry indicated the reduced population of G0/G1 phase in Znf179-knockdown cells. Second, BrdU-incorporated cells were also increased upon Znf179 knockdown. Moreover, in Znf179-knockdown cells, p35, which was known to activate CDK5 and may alter the cell cycle, and p27, a cell cycle inhibitor, were also decreased. Taken together, these lines of evidence showed that the induction of Znf179 may be related to p35 expression and p27 protein accumulation, which allowed cell cycle arrest in the G0/G1 phase, and was critical for neuronal differentiation of P19 cells.

中文摘要	I
Abstract	Ⅱ
Acknowledgment 	Ⅲ
Contents	Ⅳ
Figure index	Ⅸ
Table index	ⅹⅰ
Appendix index	ⅹⅱ
Abbreviations 	ⅹⅲ
I.Introduction	1
1 Cell cycle and cell cycle regulators	1
1.1. Cell cycle	1
1.2. Cyclin-dependent kinases 	1
1.3. Retinoblastoma/E2F pathway	2
2. Cell cycle regulation and neuronal differentiation	3
2.1. Neuronal development	3
2.2. Cell cycle exit and neuronal differentiation	3
2.3. Cell cycle-related neuronal death 	4
3. CDK5/p35 complex	5
4. Znf179	6
5. P19 embryonal carcinoma cells	7
6. Hypothesis	7
7. Specific aims	7
II. Materials and methods	9
1. Materials	9
2. Methods13
2.1. Animals	13
2.2. P19 cell neuronal differentiation	13
2.3. Primary cultures of mouse cerebellar granular cells	14
2.4. Western blot analysis	14
2.5. Immunofluorescence	14
2.6. Antibody	15
2.7. Fractionation of cytosolic and nuclear proteins 	15
2.8. Flow cytometric analysis of cell cycle distribution 	16
2.9. BrdU incorporation assay	16
2.10. Cell viability assay16
2.11. DNA microarray and Ingenuity pathway analysis	17
2.12. Reverse transcription (RT) and quantitative (q) real-time PCR assays	17
2.13. In situ hybridization 	17
2.14. Lentivirus production and transduction 	18
III. Results   	20
1. Expression and distribution patterns of Znf179 in mouse brain 	20
1.1 Generation of Znf179 antibody  	20
1.2. Notable expression of Znf179 in adult mouse brain 	20
1.3. Localization of Znf179 transcripts in developing mouse brain  	20
2. Znf179 is increased during RA-induced P19 cells neuronal 	
      differentiation  	21
2.1. Establishment of neuronal differentiation cell model by using P19	
         cells 	21
2.2. Znf179 is elevated during RA-induced P19 cells neuronal 	
          differentiation 	21
3. Znf179 protein localizes in cytosolic and nuclear compartments of 	
      neuornally differentiated P19 cells 	21
4. Inhibition of Znf179 induction significantly suppresses neuronal 	
      differentiation of P19 cells 	22
4.1. Attenuation of Znf179 expression in P19 cells by lentivirus-mediated RNA interference 	22
4.2. Inhibition of Znf179 expression attenuates neuronal differentiation 	
         of P19 cells 	22
4.3. Knockdown Znf179 also affects cell viability of P19 cells after plating 	23
5. Znf179 is required for neuronal differentiation and glial differentiation of primary granular cells 	23
5.1. Znf179 is expressed predominantly in MAP2-positive cells 	23
5.2. Inhibition of Znf179 expression attenuates neuronal differentiation of primary granular precursors 	23
5.3. Suppression of Znf179 expression also affects glial differentiation primary granular precursors 	24
6. Identification and functional annotation of differentially expressed 	
      genes in P19 cells upon Znf179 knockdown 	24
6.1. Gene expression profiling in Znf179-knockdown cells 	24
6.2. Functional annotation of differentially expressed genes 	25
7. Cell cycle exit during P19 cells neuronal differentiation………………	25
8. Knockdown of Znf179 alters cell cycle profiles and the expression of 	
      cell cycle regulators during P19 cells neuronal differentiation 	25
8.1. RA-induced P19 cells cell-cycle arrest is obstructed upon Znf179 knockdown  	25
8.2. Temporal expression pattern of cell cycle modulators in neuronal differentiation	26
8.3. Knockdown Znf179 alters the expression of p35 and p27 protein level	26
9. Identification of p35 as one of the downstream mediators of Znf179 involves in P19 cells neuronal differentiation	27
9.1. Similar phenotypes are identified in p35 and Znf179-knockdown cells	27
9.2. Re-expression of p35 partially rescues the defects in neuronal differentiation by Znf179-knockdown	27
IV. Discussion	28
1. Functions of Znf179 in neuronal differentiation  	28
2. Mechanisms of Znf179 leading to cell cycle exit 	28
2.1. p27 pathway  28
2.2. p35 pathway  29
2.3. E2F is a potential downstream effector of Znf179 involving in cell cycle exit	29
3. Mechanism of Znf179 regulating p27 protein accumulation	29
3.1. CDK5/p35 complex is not responsible for p27 protein level in Znf179-knockdown cells.	29
3.2. Other possible mechanisms modulating p27 protein level in Znf179-knockdown cells    30 
4. Mechanisms of Znf179 modulating p35 expression	30
5. Other differentially expressed genes in Znf179-knockdown cells 	31
5.1. Znf179 may involve in neurite outgrowth	31
5.2. Znf179 may involve in synaptic function	32
6. Cell identity of Znf179-expressing cells	32
7. Functions of Znf179 in neurodegenerative diseases	33
7.1. The role of Znf179 in Smith-Magenis syndrome	33
7.2. The role of Znf179 in cell cycle reentry in neurodegenerative diseases	33
7.3. Investigation of the functions of Znf179 in vivo	33
8. Concluding remarks	33
V.References	35
VI.Figures	44
VII.Tables	68
VIII.Appendixes	75
IX.Publications	78
X. Curriculum vitae  	79

                                    

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