訊息蛋白SH2B1β透過與IRSp53及Eps8交互作用促進海馬迴神經細胞的絲狀偽足形成及樹突分支

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研究生：	陳建任 Chen, Chien-Jen
論文名稱：	訊息蛋白SH2B1β透過與IRSp53及Eps8交互作用促進海馬迴神經細胞的絲狀偽足形成及樹突分支 SH2B1β enhances filopodium formation and dendritic branching of hippocampal neurons through interacting with IRSp53 and Eps8
指導教授：	陳令儀 Chen, Linyi
口試委員:	陳慧諴 Hwei-Hsien Chen 黄兆祺 Eric Hwang 高茂傑 Mou-Chieh Kao 彭明德 Ming-Der Perng
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2014
畢業學年度：	102
語文別：	英文
論文頁數：	100
中文關鍵詞：	SH2B1β 訊息蛋白、神經軸生長、樹突分支、絲狀偽足、IRSp53 蛋白、Eps8 蛋白
外文關鍵詞：	SH2B1β adapter protein, neurite outgrowth, dendritic branching, filopodium, IRSp53, Eps8
相關次數：	點閱：2 下載：0
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SH2B1為一訊息蛋白可啓動PC12細胞、皮質及海馬迴神經細胞的神經軸生長(neurite outgrowth)。在本論文研究中，我們推測大量表現SH2B1β啓動海馬迴神經細胞的絲狀偽足(filopodium) 及樹突分支(dendritic branching)的形成。在神經軸起始時(neurite initiation)，絲狀偽足的形成是必需的，微小管(microtubule)會沿著絲狀偽足延伸出去，推測SH2B1β也許藉由調控肌動蛋白的重組(actin-remodeling)，進而促進神經軸起始及生長。為進一步了解SH2B1β如何影響神經軸形成，調控肌動蛋白重組的IRSp53及Eps8蛋白被研究是否與SH2B1β有協同作用。IRSp53為一具有不同功能區域(multi-domain)的蛋白，可調控肌動蛋白細胞骨架的相關蛋白並導致絲狀偽足形成。Eps8具有結合在肌動蛋白的正端(barbed-ends)活性而調控肌動蛋白的動態。藉由活化的Cdc42調控，促使IRSp53-Eps8複合體的形成，可導致肌動蛋白束(actin bundles)的形成，進而促進絲狀偽足的突起。我們發現SH2B1β透過proline-rich區域與IRSp53及Eps8結合。大量表現SH2B1β與IRSp53可增強絲狀偽足形成及神經軸起始。相反的，藉由shRNA抑制內源性的SH2B1或表現缺少proline-rich區域的SH2B1β突變型皆會抑制絲狀偽足及神經軸分支形成。除此之外，SH2B1β、IRSp53及Eps8共同表現在細胞膜上，利用Triton X-100分離出不溶的細胞骨架部份，三者表現量隨著神經細胞發育而增加。從這些結果推測藉由啓動肌動蛋白聚合(actin polymerization)，進而促使絲狀偽足形成、神經軸起始及分支，SH2B1β、IRSp53及Eps8彼此間的交互作用是必需的。

SH2B1 is an adapter protein that promotes neurite outgrowth of PC12 cells, cortical and hippocampal neurons. In this study, we provide evidence suggesting that overexpression of SH2B1β promotes filopodium formation and dendritic branching of hippocampal neurons. In neurite initiation, filopodium formation is required and microtubule extension into filopodia, suggesting that SH2B1β may regulate actin remodeling to enhance neurite initiation and outgrowth. To understand how SH2B1β may affect neurite formation, the collaborative efforts of SH2B1β with two actin-remodeling proteins, IRSp53 (Insulin receptor tyrosine kinase substrate p53) and Eps8 (Epidermal growth factor receptor kinase substrate 8) have been investigated. IRSp53 is a multi-domain protein that can regulate actin cytoskeleton-associated proteins and thus filopodium formation. Eps8 regulates actin dynamics through actin barbed-ends capping activity. The formation of IRSp53-Eps8 complex, regulated by active Cdc42, contributes to the formation of actin bundles, thus promoting filopodium protrusions. We found that the proline-rich domains of SH2B1 interact with IRSp53 and Eps8. Overexpressing SH2B1β and IRSp53 enhanced filopodium formation and neurite initiation. In contrast, shRNA for SH2B1 to silence endogenous SH2B1 or the deletion mutants of SH2B1β which lack the proline-rich domains that inhibit filopdium formation and neuronal branching. In addition, SH2B1, IRSp53 and Eps8 co-localize at the plasma membrane and their levels increase in the Triton X-100-insoluble fraction of developing neurons. These results suggest that the interaction among SH2B1, IRSp53 and Eps8 is required to promote actin polymerization and thus filopodium formation, neurite initiation and neuronal branching.

Abstract    I
摘要    II
誌謝    III
Index    VII
Abbreviationss    XI
Introduction    1
Neural differentiation of embryonic stem cells    1
Morphogenesis of hippocampal neurons    2
Neurite initiation and outgrowth    3
Formation of filopodia    4
Role of IRSp53 in filopodium formation and neurite outgrowth    6
SH2B family members and neurite outgrowth    8
Role of Eps8 in actin cytoskeleton remodeling    11
Materials and Methods    14
Reagents    14
DNA constructs    15
Animal handling. Ethics statement.    16
Primary neuron culture    16
PC12 cells and 293T cells culture    17
Reverse transcription-polymerase chain reaction (RT-PCR)    17
Knockdown of endogenous SH2B1, IRSp53 and Eps8    18
Western blotting    18
Imunoprecipitation    19
Immunofluorescence staining    20
Triton X-100 cytoskeleton extraction    20
Subcellular fractionation    21
Duolink in situ proximity ligation assay (PLA)    22
Measurement of attachment or end points, axon length and Pearson’s correlation coefficient    22
Statistical analysis    23
Results    24
The β isoform of SH2B1 is the major isoform during the development of hippocampal neurons    24
SH2B1β increases branches of neurite in development of hippocampal neuron    25
Knock-down of SH2B1 expression reduces neurite outgrowth in development of hippocampal neuron    26
SH2B1 interacts with IRSp53 and Eps8 in neurons    26
IRSp53 and Eps8 enhance NGF-induced filopodia initiation and neurite outgrowth    28
SH2B1β enhances filopodia initiation and neurite outgrowth in overexpressing PC12-IRSp53 or PC12-IRSp53+Eps8 stable cells    29
IRSp53 and Eps8 are required for SH2B1β-mediated neurite outgrowth    30
Distribution of SH2B1, IRSp53 and Eps8 in detergent soluble and insoluble fractions    30
The proline-rich domains of SH2B1β are required to enhance filopodium formation and neurite outgrowth in hippocampal neurons    32
The N-terminal proline-rich domains of SH2B1β are required for enhancing IRSp53-induced neurite outgrowth    33
The SH2B1β and IRSp53 synergistically regulate the formation of dendritic and axonal filopodia    34
The proline-rich domains of SH2B1β interact with IRSp53 and Eps8    35
Working model of SH2B1 promotes filopodia formation and neurite outgrowth through interacting with IRSp53 and Eps8    36
Discussion    37
Figures    42
Figure 1. The β isoform of SH2B1 is the major isoform during the development of hippocampal neurons.    42
Figure 2. SH2B1β increases branches of neurite in development of hippocampal neuron.    44
Figure. 3 Knock-down of SH2B1 expression reduces neurite outgrowth in development of hippocampal neuron.    46
Figure 4. SH2B1β interacts with IRSp53 and Eps8 in neurons.    48
Figure. 5 IRSp53 and Eps8 enhance NGF-induced filopodia initiation and neurite outgrowth.    49
Figure 6. SH2B1β enhances filopodia initiation and neurite outgrowth in overexpressing PC12-IRSp53 or PC12-IRSp53+Eps8 stable cells.    51
Figure 7. IRSp53 and Eps8 are required for SH2B1β-mediated neurite outgrowth.    53
Figure 8. SH2B1β enhances F-actin assembly through interacting with IRSp53 and Eps8 in neuronal differentiation.    55
Figure 9. The proline-rich domains of SH2B1β are required to enhance filopodium formation and neurite outgrowth in hippocampal neurons.    57
Figure 10. The N-terminal proline-rich domains of SH2B1β are required for enhancing IRSp53-induced neurite outgrowth during neuronal differentiation.    59
Figure 11. The SH2B1β and IRSp53 synergistically regulate the formation of dendritic and axonal filopodia during neurite outgrowth.    61
Figure 12. The proline-rich domains of SH2B1β may interact with SH3 domain of IRSp53 and Eps8.    63
Figure 13. Working model of SH2B1 promotes filopodia elongation and neurite outgrowth through interacting with IRSp53 and Eps8.    65
Appendix    66
Figure A1. Overexpressing SH2B1β and IRSp53 regulate morphology of 293T cells.    66
Figure A2. Overexpressing SH2B1β(R555E) or SH2B1β(9YF) and IRSp53 regulate morphology of 293T cells.    67
Figure A3. The β isoform of SH2B1 specifically enhanced IRSp53-induced filopodium formation in 293T cells.    68
Figure A4. Overexpressing SH2B1β and IRSp53 regulate morphology of COS7 cells.    69
Figure A5. SH2B1β and IRSp53 co-regulate actin filament and microtubule dynamics in 293T cells.    70
Figure A6. SH2B1β and IRSp53 colocalize on the filopodia and cellular surface in 293T cells.    71
Figure A7. The N-terminal proline rich domains of SH2B1β are required to enhance IRSp53-induced filopodium formation and microtubules extending.    72
Figure A8. Overexpressing SH2B1β and Eps8 regulate morphology of 293T cells.    73
Figure A9. Overexpressing SH2B1β and Eps8 regulate morphology of COS7 cells.    74
Figure A10. SH2B1β and Eps8 colocalize on the cellular surface in 293T cells.    75
Figure A11. SH2B1β interacts with IRSp53 and Eps8 in 293T cells.    76
Figure A12. SH2B1β and Eps8 co-regulate actin filament and microtubule in 293T cells.    77
Figure A13. SH2B1β colocalizes with IRSp53 and Eps8 on the filopodia and cellular surface in 293T cells.    78
Figure A14. Subcellular distribution of SH2B1β(ΔNLS, ΔNES andΔNLS/NES) in 293T cells.    80
Figure A15. Subcellular distribution of SH2B1β(ΔNLS, ΔNES and ΔNLS/NES) when co-overexpressing with IRSp53 or Eps8 in 293T cells.    81
Figure A16. Overexpressing IRSp53 and Eps8 enhance NGF-induced filopodia initiation and neurite outgrowth in PC12 cells.    82
Figure A17. Overexpressing GFP-SH2B1β enhances NGF-induced neural differentiation of PC12-Eps8+IRSp53 stable cells.    83
Figure A18. SH2B1β enhances filopodium formation and neurite outgrowth in overexpressing PC12-Eps8+IRSp53 stable cells.    85
Figure A19. Removal SH2B1 reduced neurite outgrowth during development of PC12 cells.    86
Figure A20. SH2B1β enhances F-actin assembly in neural differentiation of PC12 cells.    87
Figure A21. IRSp53 and Eps8 enhance NGF-induced neurite outgrowth without increasing MEK-ERK1/2 signaling pathway.    88
Figure A22. The β isoform of SH2B1 is the major isoform during the development of primary neurons.    89
Figure A23. SH2B1 colocalizes with IRSp53 or Eps8 in neural differentiation.    90
Figure A24. SH2B1β and IRSp53 enhances filopodium formation and neurite outgrowth.    91
Figure A25. Knock-down of IRSp53 expression reduces neurite outgrowth in development of hippocampal neurons.    92
Figure A26. SH2B1 interacts with PSD95 in neurons.    93
Reference    94











                                

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