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Abelson interacting protein (Abi) Regulation of Notch-Mediated Hematopoiesis
조혈과정에서 Abelson 상호작용 단백질인 Abi에 의한 Notch 신호전달의 조절

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dc.contributor.advisor이승복-
dc.contributor.author박선영-
dc.date.accessioned2019-10-21T03:41:47Z-
dc.date.available2019-10-21T03:41:47Z-
dc.date.issued2019-08-
dc.identifier.other000000157615-
dc.identifier.urihttps://hdl.handle.net/10371/162441-
dc.identifier.urihttp://dcollection.snu.ac.kr/common/orgView/000000157615ko_KR
dc.description학위논문(박사)--서울대학교 대학원 :자연과학대학 협동과정 뇌과학전공,2019. 8. 이승복.-
dc.description.abstractAbelson interacting protein (Abi) is a component of the SCAR complex and transmits small GTPase Rac1 signaling to the Arp2/3 complex, triggering actin assembly. Previous reports have demonstrated that Abi and SCAR are critical for Rac-dependent membrane protrusion and macropinocytosis. In addition, Abi regulates actin polymerization through the signaling cascade involving another small GTPase molecule, Cdc42, and its downstream effector, the WASp protein. However, it has not been elucidated the biological significance of actin regulation of Abi via Cdc42-WASp. Here, I investigated the Abi influences on hematopoiesis in Drosophila. Expression data demonstrated that Abi acts cell-autonomously in hematopoiesis. Loss of Abi led to a substantial decrement in the crystal cell population and downregulation of Notch response element in the late third instar larval stage. Genetic studies revealed that abi and notch interact to participate in the differentiation process of crystal cells. These results implicate that Abi is essential for transdifferentiation to crystal cells via positive modulation of Notch signaling. For controlling of Notch signaling, Abi promotes clathrin-dependent endocytosis of Notch receptor by actin regulation through Cdc42-WASp pathway rather than Rac1-SCAR pathway. My research on identifying the physiological function of Drosophila Abi in hematopoiesis will serve as fundamental data for the pathophysiological study of myeloproliferative neoplasms exhibiting the loss of human Abi.-
dc.description.abstractAbi 단백질은 Abelson 상호작용 단백질로 명명되었으며, SCAR 복합체를 구성하는 요소로 small GTPase 중의 하나인 Rac1 신호전달을 Arp2/3 복합체로 전달하여 actin의 중합화를 촉진한다. 이전 연구에 따르면 Abi와 SCAR가 Rac에 의존하는 세포막 돌출과정과 macropinocytosis에 작용한다고 알려져 있다. Abi는 actin 중합화에 있어, SCAR 외에 WASp 단백질을 통해서도 이를 촉진한다고 알려졌으며, 이 때에는 Rac1이 아닌 Cdc42가 신호전달을 매개한다. 하지만 Cdc42-WASp 경로를 통한 Abi의 actin 조절이 가지는 생물학적 의미에 대해서는 규명된 바가 미미하다. 본 논문은 초파리의 Abi가 혈액세포 발생과정인 조혈과정에 미치는 영향에 대한 것이다. Abi 단백질은 혈액세포인 plasmatocyte와 crystal cell에서 발현하며, abi 돌연변이체 유충은 late third instar 단계에서 crystal cell의 수가 감소하고 Notch reporter인 NRE의 발현이 현저하게 줄어들어 있는 것을 발견하였다. 유전학적 연구를 통해 abi와 notch가 상호작용하여 crystal cell의 분화과정에 관여한다는 것을 확인하였으며, 이러한 결과들로 Abi가 Notch 신호전달을 조절하여 plasmatocyte에서 crystal cell로의 전환분화(transdifferentiation) 과정에 필수적으로 작용한다는 것을 증명하였다. 또한 Abi는 Notch 신호전달을 위해 Notch 수용체의 clathrin-dependent endocytosis를 촉진하는데 이 때에 Rac1-SCAR 신호전달보다는 Cdc42-WASp 신호전달을 활성화시켜서 actin을 조절한다는 것을 밝혔다. 따라서 본 연구는 초파리 모델을 이용하여 조혈과정에서 Abi의 생리적 기능을 규명한 것으로, 사람에서 Abi 단백질의 결손이 발견되는 골수증식성 종양의 병리학적 기전 연구에 활용될 수 있는 기초자료로서 충분한 가치가 있을 것으로 사료된다.-
dc.description.tableofcontentsAbstract 1
Table of Contents 3
List of Figures 5
Abbreviations 7
Introduction 11
1. Drosophila melanogaster as a model system of hematopoietic development 11
2. The characteristics of Abi proteins and their roles in hematopoiesis 17
3. Purpose of research 25
Materials and Methods 27
Fly stocks 27
Larval staging and analysis 28
Molecular Biology 28
Hemocyte counting and statistical analysis 29
Live imaging and analysis 30
Crystal cell visualization and analysis 30
Hemocyte immunostaining 31
Cell culture and transient transfections 32
Antibody feeding assay 33
Wounding assay 33
Statistical analysis 34
Results 37
1. Loss of Abi leads to hematopoietic defects 37
2. Abi regulates transdifferentiation of plasmatocytes into crystal cells 43
3. Abi is required for the crystal cell differentiation in larval stages 53
4. Determination of the Abi expression in hemocytes 57
5. Abi positively regulates Notch signaling 60
6. Genetic interaction between abi and notch for regulating crystal cell population 64
7. Abi and WASp interaction for maintaining sessile crystal cell population 76
8. Clathrin-dependent endocytosis is required for Abi-mediated Notch signaling 84
9. Serrate-induced Notch internalization is altered by knockdown of abi 99
10. Abi functions in scab formation 104
Discussion 108
1. Abi functions in hemocyte differentiation during hematopoiesis 108
2. The role of Abi in the regulation of signaling pathway through endocytosis 110
References 116
국문초록 131
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dc.language.isoeng-
dc.publisher서울대학교 대학원-
dc.subjectAbi-
dc.subjectNotch signaling-
dc.subjectCrystal cell-
dc.subjectTransdifferentiation-
dc.subjectEndocytosis-
dc.subjectHematopoiesis-
dc.subject.ddc611.81-
dc.titleAbelson interacting protein (Abi) Regulation of Notch-Mediated Hematopoiesis-
dc.title.alternative조혈과정에서 Abelson 상호작용 단백질인 Abi에 의한 Notch 신호전달의 조절-
dc.typeThesis-
dc.typeDissertation-
dc.contributor.AlternativeAuthorSun-Young Park-
dc.contributor.department자연과학대학 협동과정 뇌과학전공-
dc.description.degreeDoctor-
dc.date.awarded2019-08-
dc.identifier.uciI804:11032-000000157615-
dc.identifier.holdings000000000040▲000000000041▲000000157615▲-
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College of Natural Sciences (자연과학대학)Program in Brain Science (협동과정-뇌과학전공)Theses (Ph.D. / Sc.D._협동과정-뇌과학전공)
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