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研究生:曾振圓
研究生(外文):Chen-Yuan Tseng
論文名稱:Notch訊息傳遞及其下游目標基因snail於果蠅卵巢幹細胞之功能性探討
論文名稱(外文):Control of Drosophila Ovarian Stem Cell by Notch Signaling and Its Target, Snail
指導教授:許惠真
指導教授(外文):Hwei-Jan Hsu
口試委員:鐘邦柱楊慕華許惠真皮海薇姚季光
口試委員(外文):Bon-Chu ChungMuh-Hwa YangHwei-Jan HsuHai-Wei PiChi-Kuang Yao
口試日期:2015-12-28
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2015
畢業學年度:104
語文別:英文
論文頁數:116
中文關鍵詞:果蠅卵巢幹細胞
外文關鍵詞:DrosophilaOarian Stem CellNotch signalingSnail
相關次數:
  • 被引用被引用:0
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幹細胞的維持是透過本身與來自外在的環境訊息所調控,其中這特化的環境我稱之為niche,它提供了幹細胞與其結合的能力並分泌維持幹細胞本身所需的訊息因子進而維持生物體本身組織的恆定。幹細胞不正常的分化及增生往往會導致組織的退化或形成癌細胞。然而,是甚麼樣的訊號或因素導致此原因仍然尚未清楚。在本論文我們發現Notch signaling及它的下游目標基因snail透過不同的機制下,扮演了維持卵巢幹細胞的恆定性。在卵母幹細胞,我們發現Notch signaling會隨著年紀的增長而增加,並且導致卵母幹細胞離開niche。透過誘導Notch 以及其相關調控基因frine突變的卵母幹細胞會維持在niche時間較久以及具有高度的競爭性,並且會高度表達E-cadherin。E-cadherin是最主要幫助卵母幹細胞與其niche結合的重要因子。我們也利用GAL4-UAS系統再次的證明在老化過程中,增加或抑制Notch signaling 在卵母幹細胞上會影響與niche結合性,透過的就是E-cadherin。而Notch signaling在老化過程中增加,有一部分是受到Sex lethal 所調控的。Notch signaling在過去文獻發現在niche也扮演的維持細胞特性的重要腳色,這說明了Notch signaling對於幹細胞外在及內部的調控都扮演了維持幹細胞特性的。
在進一步了解Notch signaling是如何抑制E-cadherin中,我們更發現其中一突變果蠅Scutoid (Sco),過去被認為是高度活化snail基因的突變種。也是Notch signaling下游基因,同樣地導致卵母幹細胞離開其niche這說明Notch signaling可能隨著老化過程中進而活化Snail進而抑制E-cadherin的表現。另外我們利用了Sco突變果蠅研究另一類型卵巢表皮幹細胞(Follicle stem cell, FSC).透過誘導方式產生出Sco mutant FSC發現了與卵母幹細胞不同的結果。Sco突變會影響FSC維持在其niche時間較久並且增加其增生速度,而其子細胞follicle cells也因高度增生的關係抑制分化及失去了細胞的極性,這分化包含了細胞分裂週期由增生轉為內增生。然而,透過GAL4-UAS系統高度表達snail在follicle cells並不會導致類似Sco突變的結果使得細胞無法正常分化而增生,而是導致FSC高度增生。另一方面透過snail突變以及以RNAi 抑制snail實驗中發現幹細胞增生速度減緩這說明了Sail可能扮演了對於FSC細胞週期扮演著重要的調控者,與其他研究結果不同的是,Snail並不會透過E-cadherin的抑制去調控幹細胞的增生,這項結果顯示Snail除了參與細胞的移動(epithelial and mesenchymal transition (EMT))之外,也會在幹細胞上透過其他調控方式,扮演著不同的功能。 我們發現了Notch signaling與Snail在幹細胞扮演以往不一樣的功能。透過這項研究,能幫助我們更了解Notch signaling-Snail在轉移性癌症可能引起癌症幹細胞的產生。
Stem cells are housed by a microenvironment, or called niche, which provides physical contact and self-renewal signals to control stem cell homeostasis. Inadequate stem cell proliferation and differentiation often associate with tissue degeneration or tumorigenesis. However, the detail mechanisms underlying these processes remain unclear. Here, we found that Notch signaling and its downstream target, Snail, differentially regulates ovarian germline stem cells (GSCs) and epithelial follicle stem cells (FSCs) in Drosophila. In GSCs, Notch signaling regulated by Sxl lethal suppresses E-cadherin expression (mediates GSC-niche anchorage) in response to aging. It has been shown that Snail, a direct target of Notch signaling, suppresses E-cadherin for cell movement and generating cells with stem cell property, suggesting the role of Snail in the Sxl-Notch-E-cadherin regulatory axis to control GSC aging. Indeed, increased Snail activity in GSCs by generating GSCs homozygous mutant with Scutoid (Sco), a snail hypermorphic allele originated from X-ray-induced chromosome transposition, results in a quick loss of GSCs. In contrast to GSCs, FSCs with excessive Snail (Sco mutant or snail-overexpressing FSCs) are hyper-proliferative with prolonged maintenance, whereas, mutation of snail in FSCs only compromises their proliferation. Consistently with other studies that Snail suppresses E-cadherin expression in FSCs; however suppression of E-cadherin expression in snail mutant FSCs cannot restore their low rate of proliferation, suggesting that Snail controls FSC proliferation independently of E-cadherin. These results show that Notch signaling and its downstream Snail play a new role in the regulation of stem cell behavior, and that provides a great platform to dissect mechanisms underlying Notch-related diseases (including stem cell aging) and relevant to cancer stem cell transformation.
I
Contents
Abstract in Chinese
1
Abstract
2
Background
3
Notch signaling in stem cell regulation
3
Snail family in stem cell function
4
The Drosophila ovary for studying stem cell behavior
5
Niche-derived signals from niche maintain ovarian stem cells
6
Functional decline of germline stem cells during aging
8
Replacement of ovarian stem cells
9
Results
11
Notch signaling mediates the age-associated decrease in adhesion of germline stem cells to the niche.
Notch is not directly required for GSC maintenance and division
11
GSCs with low levels of Notch signaling exhibit increased GSC competitiveness and niche occupancy
13
Notch signaling controls of long-term maintenance, independently of BMP signaling
14
Notch signaling in GSCs suppresses physical contact to their niche
15
E-cadherin is sufficient for Notch signaling-mediated GSC competition
16
Notch signaling is increased in aged GSCs
17
Sex lethal negatively represses Notch signaling in GSCs
18
Modulation of Sxl-Notch signaling in GSCs alters GSC lifespan
19
Snail Controls Proliferation of Drosophila Ovarian Epithelial Follicle Stem Cells, Independently of E-cadherin
Sco mutant FSCs exhibit hyperproliferation and enhanced maintenance
22
Sco mutant follicle cells fair to enter mitotic cycle-endocycle transition
23
Sco mutant follicle cells exhibit hyper-proliferation
24
II
Notch signaling is decreased in out-layers of Sco mutant follicle cells
25
Sco mutant follicle cells lose polarity in anterior and posterior poles of egg chambers
26
Snail negatively regulates E-cadherin expression in follicle cells
27
Snail is not involved in follicle cell outgrowth induced by Sco mutation
28
Snail controls FSC proliferation independently of its known role on E-cadherin
30
Discussion
33
Uneven Notch signaling in stem cells triggers complex cellular events that are in a context-dependent manner
33
Notch signaling contributes to age-related diseases
33
Aging may trigger stem cell competition via Notch signaling activation
34
The dual role of Sxl in GSC self-renewal/differentiation
35
The possible regulatory mechanism of Sxl-mediated GSC aging
36
Sco mutant provides a potential model by which to study the coordination of follicular epithelial proliferation and differentiation
37
Snail regulates cancer stem cells and stem cells through EMT-dependent and independent roles
38
Proliferation/or adhesive ability is sufficient to support follicule epithelial stem cell maintenance
The possible upstream or downstream targets of Snail-mediated FSC proliferation
39
40
Methods and materials
44
Fly stocks and culture
44
Genetic mosaic assay
45
III
Immunostaining and fluorescence microscopy
46
Signal analysis in GSCs and FSCs
47
Edu incorporation
48
Western blotting analysis
49
Isolation of GSC by FACS
50
Microarray and quantitative (q)-PCR
50
Figures and Figure legends
53
Tables
102
Publication
115
Honor
116
List of Figure
Figure 1. E(spl)m7-lacZ is expressed in niche cap cells and GSCs
53
Figure 2.E(spl)m7-lacZ represent Notch signaling activity in GSCs
54
Figure 3.Loss of N or fng enhance GSC maintenance without affecting mitotic activity
55
Figure 4. Rumi is not required for GSC maintenance.
57
Figure.5 Apoptosis is not enhanced in N or fng mosaic germaria
58
Figure.6 BMP signaling levels is comparable among control, N and fng mutant GSCs
59
Figure 7. The level of Notch signaling in GSCs controls E-cadherin expression and contact area in GSC-niche junctions
60
IV
Figure 8. E-cadherin expression and contact area are increased in fng mutant GSC-niche junctions
Figure 9. Notch signaling negatively regulates E-cadherin expression in GSCs
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64
Figure 10. Notch signaling controls GSC-niche adhesion via E-cadherin
65
Figure 11. Notch signaling is increased in GSCs with age
67
Figure 12.E-cadherin is significantly reduced in age GSC
68
Figure 13. Su(H)Gbe-lacZ expression is increased in GSCs with age
69
Figure 14. Notch ligands, Delta and Serrate, are not reduced in aged GSCs
70
Figure 15. Sxl negatively regulate Notch signaling in GSC
71
Figure 16. Suppression of sxl in niche cells does not affect Notch signaling in cap cells and GSCs
Figure 17. Sxl controls GSC maintenance and differentiation
Figure 18. Sxl is decreased in GSC with aged
Figure 19. Sxl expression is absent in sxl- knock down GSCs, and is weakly expressed in germ cells with age
Figure 20.Modulation of Notch signaling alters aged-dependent GSC loss
Figure 21. Manipulation of Notch signaling in GSCs alters their maintenance with age
Figure 22. GSCs resided in the niche express different levels of E(spl)m7-lacZ
Figure 23. Sco mutation decreases half-life of GSCs but enhances FSC maintenance and proliferation
Figure 24. E-cadherin expression is increased in Sco mutant FSCs
Figure 25. Prefollicle cells derived from Sco mutant and snail-overexpressing FSCs exhibit increased number
Figure 26. Sco mutant prefollicle cells show intercalation and ME transition defects
Figure 27. Notch signaling and its targets are reduced in outer-layers of Sco mutant follicle cells
Figure 28. Sco mutation causes cell polarity loss in follicle cells delaminated from the epithelial layer
Figure 29. E-cadherin is down regulated in Sco mutant and snail-overexpressing follicle cells
Figure 30. Knock down of snail expression rescues the bristle loss phenotype in Sco mutants
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90
V
Figure 31. Snail is not sufficient to cause ME defects of Sco mutant follicle cells
Figure 32. Non oclei and Snail are dispensable for the induction of multiple-layered follicle cells in Sco mutants
Figure. 33. Snail is not essential for Sco-induced multiple-layer formation
Figure 34. Knockdown of genes that located at the Sco chromosome does not result in multipled-layered follicle cells
Figure 35. Snail directly controls FSC proliferation, but not maintenance
Figure 36. Snail directly controls FSC mitotic activity independently of E-cadherin suppression
Figure 37. Schematic of Notch signaling and Snail in Drosophila ovarian stem cell regulation
List of Tables
Table S1. Notch signaling controls GSC competition for niche occupancy via E-cadherin.
Table S2. Snail controls follicle stem cell proliferation
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