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研究生：	謝崇斌 Hsieh, Chung-Pin
論文名稱：	CD47在小腦顆粒細胞發育與髓母細胞瘤細胞複製所扮演的角色 The role of CD47 in cerebellar granule cell development and medulloblastoma cell proliferation
指導教授：	黃阿敏 Huang, A-Min
學位類別：	博士 Doctor
系所名稱：	醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences
論文出版年：	2015
畢業學年度：	103
語文別：	英文
論文頁數：	93
中文關鍵詞：	CD47 、小腦顆粒細胞、細胞複製、遷移、神經突分化、社交行為、憂鬱行為、髓母細胞瘤、c-Myc 、MAPK
外文關鍵詞：	CD47, cerebellar granule cells, proliferation, migration, neurite differentiation, social behavior, depression, medulloblastoma, c-Myc, MAPK
相關次數：	點閱：120 下載：2
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CD47是一種細胞膜類免疫球蛋白受器，具有調節神經細胞分化的功能。然而CD47在小腦發育及小腦相關疾病所扮演的角色，仍多所未知。本研究第一部份，探討CD47在小腦發育及相關行為之角色。首先以原位雜交法觀察CD47 mRNA在小鼠腦發育過程的表現，發現CD47 mRNA大量表現在發育中的小腦，尤其是小腦顆粒細胞。CD47蛋白質明顯表現在小腦外顆粒層之內層、分子層與內顆粒層，這些區域分別存在著終止複製、遷移與神經突分化中的顆粒細胞。利用CD47基因剃除小鼠，發現在顆粒細胞細胞複製增加、遷移受阻、軸突與樹突數目與分支的減少。CD47基因剃除小鼠也顯示了小腦結構的異常，介於第VI與VII腦葉之間的腦溝長度明顯變短。CD47基因剔除小鼠也伴隨行為的異常，出生後3週社交行為異常增加，出生後14週出現類憂鬱行為。本研究第二部份，探討CD47在小腦腫瘤細胞複製之角色。在人類髓母細胞瘤Daoy細胞中，CD47基因knockdown會促進細胞複製。相反的，大量表現CD47或活化CD47皆有效減少Daoy細胞的複製。活化CD47也明顯降低致癌基因c-Myc mRNA與蛋白質表現，而MAPK抑制劑則有效反轉此抑制效果。另外，CD47抗體明顯增加兩種髓母細胞瘤Daoy與VGH-MED細胞的複製，然而卻減少其他神經細胞瘤IMR32與SK-N-SH的細胞數。綜合以上結果，本研究發現，CD47可調節小腦顆粒細胞發育過程中的複製、遷徙與分化；CD47基因剔除小鼠呈現小腦結構與行為異常。另外，本研究也證實，在人類髓母細胞瘤細胞中，CD47可經由活化MAPK活性、減少c-Myc表現而抑制細胞複製；處理CD47抗體增加髓母細胞瘤複製。本研究不僅提供CD47在小腦顆粒細胞發育及小腦相關行為的角色，同時也提出CD47抗體在治療小腦腫瘤的風險。

CD47 is an immunoglobulin-like membrane protein that is known to be involved in neuronal differentiation. However, roles of CD47 in cerebellar development and relevant diseases remain poorly understood. At the first part of this study, we identify roles of CD47 in cerebellar granule cell development and related behaviors. Firstly, in situ hybridization was used to determine distribution of CD47 mRNA in the mouse brain during development. CD47 mRNA was robustly expressed in the developing cerebellum, especially in cerebellar granule cells. CD47 protein was mainly expressed in the inner layer of the external granule layer (EGL), molecular layer, and internal granule layer (IGL), where granule cells become postmitotic, start radial migration and differentiate into mature granule cells, respectively. By using CD47 knockout mice, increased proliferation, impaired migration and decreased neurite arborization including reduced number of branches in axonal collaterals and dendrites were found in cerebellar granule cells. Meanwhile, the length of the fissure between Lobules VI and VII was decreased in CD47 knockout mice. In addition, CD47 knockout mice exhibited dysfunction in behaviors including increased social interaction at P21 and depressive-like behaviors at 10 wk after birth. At the second part of this study, we characterized roles of CD47 in proliferation of medulloblastoma cells. In human medulloblastoma Daoy cells, knockdown of CD47 increased cell proliferation. On the contrary, overexpression and activation of CD47 significantly inhibited cell proliferation. Moreover, CD47 activation significantly reduced the expression level of oncogene c-Myc mRNA and protein and the inhibition be reversed by the MAPK inhibitor. In addition, anti-CD47 antibody significantly increased the proliferation in medulloblastoma cell lines Daoy and VGH-MED but decreased cell number in other neuroblastoma cells such as IMR32 and SK-N-SH cells. In summary, this study demonstrated that CD47 regulates cerebellar granule cell development including proliferation, migration and neurite differentiation, CD47 knockout mice exhibit abnormalities in cerebellar structures and atypical behaviors, CD47 inhibits proliferation of medulloblastoma cells via MAPK activation and c-Myc downregulation, and anti-CD47 antibody treatment increases proliferation of medulloblastoma. Our study not only provides roles of CD47 in cerebellar granule cell development and cerebellum relevant behaviors but also highlight the risk of the application of anti-CD47 antibody on the therapy of cerebellar tumors.

I. Introduction ............................................................................................................ 1
1. CD47 Structure and Partners........................................................................... 2
2. CD47 in Neuronal Differentiation .................................................................. 4
3. Cerebellar Granule Cell Development ............................................................ 5
4. Abnormal Cerebellar Granule Cell Development and Dysfunction in
Behaviors ............................................................................................................... 6
5. Cerebellar Granule Cell Proliferation and Medulloblastoma Formation ........ 6
6. Potential Involvement of CD47 in MB Cell Proliferation .............................. 7
7. Hypothesis ....................................................................................................... 8
8. Specific aims ................................................................................................... 8
II. Materials and Methods ........................................................................................... 9
1. Animals ......................................................................................................... 10
2. In situ hybridization ...................................................................................... 10
3. Immunohistochemistry ................................................................................. 11
4. Proliferation assay ......................................................................................... 12
4.1. CD47 knockout mice ......................................................................... 12
4.2. Primary cerebellar granule cell cultures ............................................ 12
5. Migration assay ............................................................................................. 13
5.1. Migration of newborn granule cells in CD47 knockout mice ............ 14
5.2. Cerebellar slice cultures ..................................................................... 14
5.3 Cerebellar microexplant cultures ........................................................ 15
6. Neurite differentiation analysis ..................................................................... 15
6.1. Plasmid DNA constructs .................................................................... 15
6.2. Transient transfection and 4N1K treatment ....................................... 16
6.3. Measurement of neurite parameters ................................................... 17
7. Structural analysis of cerebellar cortex ......................................................... 17
8. The 3-chamber social-behavior test .............................................................. 17
9. Open-field test ............................................................................................... 18
10. Tail-suspension test ..................................................................................... 19
11. Rotarod test ................................................................................................. 19
12. Cell cultures ................................................................................................ 19
13. Lentiviral shRNA production and infection ................................................ 20
14. Reverse transcription polymerase chain reaction (RT-PCR) ...................... 20
15. BrdU incorporation assay in MB cell lines ................................................. 21
16. Colony formation analysis .......................................................................... 22
17. 3-(4 5-dimethylthiazol-2-yl)-2 5-diphenyltetrazolium bromide (MTT) assay
....................................................................................................................22
18. AlamarBlue assay ........................................................................................ 23
19. Plasmid DNA constructs and transient transfection in Daoy cells ............. 23
20. Western blotting .......................................................................................... 24
21. Statistical analysis ....................................................................................... 25
III. Results .................................................................................................................. 26
Part I. Deficits in cerebellar granule cell development and social interactions in CD47
knockout mice ...................................................................................................... 26
1. Expression of CD47 during development ..................................................... 27
2. Expression of CD47 in developing cerebellar granule cells ......................... 28
3. Deficits in postmitotic progression of cerebellar granule cells in CD47
knockout mice ...................................................................................................... 28
4. Impaired migration of cerebellar granule cells in CD47 knockout mice ...... 31
5. Defective axonal and dendritic growth in cerebellar granule cells in CD47
knockout mice ...................................................................................................... 32
6. Effect of CD47 expression and activity on axonal and dendritic growth in
cerebellar granule cells ........................................................................................ 33
7. Diminished length of fissures between cerebellar lobules in CD47 knockout
mice. ..................................................................................................................... 34
8. CD47-deficient mice exhibit abnormal social interaction ............................ 34
9. Depressive-like behavior in CD47 knockout mice ....................................... 35
Part II. CD47 inhibits proliferation of medulloblastoma cells via MAPK activation
and c-Myc downregulation .................................................................................. 37
10. Knockdown of CD47 increased proliferation of Daoy cells ....................... 38
11. Overexpression and activation of CD47 decreased proliferation of Daoy
cells ....................................................................................................................38
12. CD47 down-regulates the expression of c-Myc but not genes downstream
of Shh and Notch signaling in Daoy cells ............................................................ 39
13. CD47 inhibits cell proliferation via the MAPK pathway in Daoy cells ..... 40
14. Differential effects of the MAPK and AKT inhibitor on c-Myc by the
treatment of 4N1K in Daoy cells and U-87 MG cells ......................................... 40
15. Anti-CD47 antibodies increased the proliferation in human MB cells but
not in other neuronal tumor cells ......................................................................... 41
IV. Discussion ............................................................................................................ 43
1. Major findings ............................................................................................... 44
2. CD47 regulates multiple stages of cerebellar granule cell development ..... 44
2.1. CD47 inhibits proliferation of cerebellar granule cells ...................... 45
2.2. CD47 is essential for migration of cerebellar granule cells ............... 47
2.3. CD47 promotes neurite differentiation in cerebellar granule cells .... 47
3. CD47 knockout mice exhibited a shorter fissure between Lobules VI and VII
....................................................................................................................48
4. CD47 knockout mice showed abnormal social and depressive-like behaviors
....................................................................................................................49
4.1. CD47 knockout mice showed abnormal social behaviors ................. 49
4.2. CD47 knockout mice exhibited depressive-like behaviors ................ 50
5. CD47 inhibits proliferation of Daoy cells ..................................................... 50
5.1. Knockdown of CD47 increases proliferation in Daoy cells .............. 50
5.2. Overexpression and activation of CD47 inhibit proliferation of Daoy
cells .............................................................................................................. 51
6. CD47 inhibits Daoy cell through MAPK signaling and c-Myc expression .. 52
6.1. Inhibition of CD47 on Daoy cell proliferation depends on
downregulation of c-Myc ............................................................................. 52
6.2. CD47 inhibits proliferation of Daoy cells via MAPK activation ...... 52
6.3. Downregulation of c-Myc mediated by CD47 depends on MAPK
activation. ..................................................................................................... 53
7. Opposite effects of anti-CD47 antibody on cell proliferation in MB and other
tumor cell lines ..................................................................................................... 53
V. Conclusion ........................................................................................................... 55
VI. Future Directions ................................................................................................. 55
VII. References ............................................................................................................ 57
VIII. Figures .................................................................................................................. 67
IX. Publications .......................................................................................................... 93
                                    

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