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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 吳益群 | |
| dc.contributor.author | Min-Ren Chiang | en |
| dc.contributor.author | 江銘仁 | zh_TW |
| dc.date.accessioned | 2021-06-08T02:26:17Z | - |
| dc.date.copyright | 2015-08-19 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-08-18 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19905 | - |
| dc.description.abstract | 細胞遷移對於生物的生長和發育相當重要。在雌雄同體的線蟲中，生殖腺(gonad)的發育型態決定於位於生殖腺兩端遠頂細胞(distal tip cell)的遷移路徑，而開啟遠頂細胞進行向背遷移的訊息則是經由Netrin的受器(receptor) UNC-5所決定，另外unc-5的表現則是由上游的轉錄因子(transcription factor) DAF-12、LIN-29以及BLMP-1所調控，先前的研究指出LIN-29和DAF-12會促進unc-5的表現，而BLMP-1則會抑制unc-5表現。我們發現調控生理時間的基因lin-42能夠促進blmp-1及抑制lin-29在發育早期的表現(L2~early L3)，來避免DTC提早進行轉彎。然而我們意外在blmp-1; daf-12的雙突變中觀察到包含正常、提早轉彎以及不轉彎的多樣(heterogeneous)突變性狀。為了探討多樣性狀的產生原因，我們利用轉錄報導基因(transcription reporter)以及單一分子螢光同位雜交法(smFISH)來觀察blmp-1是否會對lin-29及unc-5有未知的調控，結果得知blmp-1會在早期抑制lin-29的表現但是在晚期(mid L3~early L4)則是促進，此結果證實BLMP-1會經由促進lin-29進而調控unc-5的表現，而多樣性狀的產生可能是由於lin-29的不正常表現造成。我們同時建立了一個數學模擬程式來驗證lin-29及unc-5的表現形態對於性狀的影響，理論模擬的結果也顯示blmp-1;daf-12雙突變中多樣性的性狀是因為UNC-5蛋白的提早表現，以及表現較低很接近向背遷移時的閾值(threshold)所造成。我們也在特定時期調控上游lin-42的表現觀察到能提高lin-29及unc-5的轉錄，進而使UNC-5遠離閾值並降低不轉彎的性狀比例。然而我們發現在unc-5完全失去功能的突變中(null allele)，後端(posterior)的生殖線仍然有大約30%的遠頂細胞是能正常進行向背遷移，但是當daf-12和lin-29同時突變時，全部的遠頂細胞都不會進行向背遷移。由這個結果我們推測除了UNC-5以外或許還有其他調控向背遷移的引導系統(guidance system)，並且此引導系統的表現是受到DAF-12和LIN-29調控。我們利用DAF-12和LIN-29的DNA結合序列和基因功能性測試發現INA-1和MIG-6會與UNC-5共同調控遠頂細胞進行向背遷移。這項研究使遠頂細胞遷移的空間及時間調控機制更加完善，並且我們也利用基因調控機制解釋了在blmp-1; daf-12雙突變中多樣性狀產生的原因。 | zh_TW |
| dc.description.abstract | Cell migration plays an important role during animal development. In the C. elegans hermaphrodite, the shape of the gonad is determined by the migration pattern of two somatic distal tip cells (DTCs). UNC-5 is a netrin receptor that acts as a guidance cue to regulate the DTC dorsalward migration. The transcription factors DAF-12, LIN-29 and BLMP-1 act together to regulate unc-5 expression. Previous studies have shown that LIN-29 and DAF-12 suppress blmp-1 transcription and BLMP-1 negatively regulates unc-5 to control the normal timing of DTC migration. We found that LIN-42, C. elegans Period homolog, represses lin-29 transcription and activates blmp-1 transcription to prevent precocious DTC dorsal migration. Interestingly, blmp-1; daf-12 double mutants displayed a heterogeneous phenotype with a normal, precocious or retarded dorsalward turning. To investigate the causes of this heterogeneous phenotype, we used transcriptional reporter and single molecule fluorescence in situ hybridization (smFISH). We found earlier but lower lin-29 and unc-5 expression in blmp-1; daf-12 double mutants at the specific developmental stages, indicating that the early but low expression of lin-29 possibly propagates to unc-5. These data suggest that BLMP-1 may activate lin-29 expression at DTC turning stage and the heterogeneous phenotype may result from the abnormal expression of lin-29 in blmp-1; daf-12 mutants. We, therefore, developed a mathematical model to examine whether the earlier but lower lin-29 and unc-5 expression cause heterogeneous phenotype in the double mutant. The results indicated the phenotypic variation in blmp-1; daf-12 mutants may result from the lower but noisy expression level of UNC-5 near the threshold of DTC dorsalward turning. Indeed, by manipulating the upstream lin-42 regulators to increase the lin-29 and unc-5 expression, we found the heterogeneous phenotype in blmp-1; daf-12 could be alleviated. The fact that about 30% of DTCs still undergo dorsalward migration in unc-5 null allele suggests that additional guidance system besides UNC-5 exists. No DTCs makes dorsalward migration in daf-12; lin-29 double mutants, therefore, the additional guidance system may be regulated by daf-12 and lin-29. Using the binding consensus sequences of DAF-12 and LIN-29 and a functional test, we identified MIG-6 and INA-1 as components of the guidance system that act in parallel with UNC-5 to direct DTC dorsalward migration. To sum up, our studies establish a comprehensive gene regulatory network consisting of temporal and spatial regulation for the DTC dorsalward migration in C. elegans, and provide the molecular bases for the heterogeneous phenotype observed in the mutants. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T02:26:17Z (GMT). No. of bitstreams: 1 ntu-104-R02b43001-1.pdf: 11424910 bytes, checksum: 1be57a66e642999cc06de3d06b9dc225 (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 致謝 i
中文摘要 ii Abstract iv Table of Contents 1 Introduction 4 Materials and Methods 9 Strains 9 Transgenic worms 9 DNA constructs 10 RAN interference 10 Quantify the GFP reporter signal 11 Single molecule fluorescence in situ hybridization (smFISH) 11 Probes 12 Quantify the smFISH signal 12 Antibodies and immunostaining 12 Results 14 LIN-42 can activate blmp-1 expression without lin-29 during DTC phase I migration 14 LIN-42 may directly repress lin-29 transcription during DTC phase I migration 14 BLMP-1 can promote lin-29 expression during DTC dorsal turn 15 Lower lin-29 and unc-5 expression causes phenotypic heterogeneity 17 UNC-5 protein expression level correlates well with the timing of DTC dorsal turn 18 Upstream lin-42 gene fluctuation causes the no dorsal turn phenotype in blmp-1; daf-12 mutants 19 INA-1 and MIG-6 can function with UNC-5 to regulate DTC dorsal migration 20 Neither DAF-12 nor LIN-29 regulates the expression of mig-6s in DTCs 21 Discussions 23 The activation and repression of lin-29 by blmp-1 are both required for DTC dorsalward migration 23 DAF-12 may activate the transcription of lin-29 through the miRNA 24 In blmp-1; daf-12 mutants, the role UNC-5 expression on DTC dorsalward migration is not clear yet. 25 DAF-12 and LIN-29 may regulate the transcription of ina-1 and it probably affects the dorsalward migration of DTCs through mig-6 26 PAT-2 and PAT-3 may be required to work with UNC-5 to regulate DTCs dorsalward migration 28 There may exist a co-regulator that can switch the function of blmp-1 in different developmental stage 29 Figures 31 Figure 1. UNC-5/Netrin signaling pathway regulates DTCs dorsalward migration. 31 Figure 2. LIN-42 regulates blmp-1 and lin-29 in the opposite functions before the mid L3 stage. 33 Figure 3. blmp-1 activates the transcription of lin-29 to promote DTC dorsal turning after mid L3 stage. 34 Figure 4. lin-29 transcripts are reduced in blmp-1 and blmp-1; daf-12 double mutants after mid L3 in smFISH experiment. 37 Figure 5. Loss of blmp-1 results in reduced unc-5 transcription after mid L3 in the smFISH data. 38 Figure 6. The mRNA level of unc-5 cannot correlate with the DTC dorsalward migration in the smFISH data. 40 Figure 7. The protein level of unc-5 correlates well with the DTC dorsalward migration in the modeling data. 41 Figure 8. UNC-5 protein expression level correlates well with the time of dorsal turn. 44 Figure 9. Removing the residual expression of lin-42 at the lin-42-off state enhances the transcription of lin-29 and unc-5 and reduces no dorsal turning phenotype in blmp-1; daf-12 mutants. 45 Figure 10. UNC5 protein cannot be detected in DTCs of blmp-1; daf-12 mutants carrying the Punc-5::unc-5b::gfp transgene. 47 Figure 11. MIG-6 and integrin receptor can cooperate with UNC-5 guidance network to regulate the DTC dorsal migration. 49 Figure 12. A comprehensive genetic network used for the temporal and spatial control of DTC dorsalward migration. 50 Tables 51 Table 1. The regulation of LIN-42 on blmp-1 does not require LIN-29 51 Table 2. The regulation of LIN-42 on lin-29 does not require BLMP-1 52 Table 3. The genetic interaction of DTC dorsalward migration 53 Table 4. daf-12 knockout mutants have no DTC migration defect 54 Table 5. ina-1 and mig-6 cooperate with unc-5 to regulate DTC dorsal migration 55 Table 6. The expression of mig-6s is not regulated by DAF-12 and LIN-29 56 References 57 Supplementary materials 61 lin-29 smFISH probe 61 unc-5 smFISH probe 62 | |
| dc.language.iso | en | |
| dc.title | 探討線蟲中細胞遷移基因及時間和空間的調控機制 | zh_TW |
| dc.title | Characterizing the Genetic Network that Regulates the Temporal and Spatial Cell Migration in C. elegans | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 潘俊良,陳昌熙,許昭萍 | |
| dc.subject.keyword | 線蟲,細胞遷移,遠頂細胞,生殖腺, | zh_TW |
| dc.subject.keyword | C. elegans,cell migration,distal tip cell,gonad, | en |
| dc.relation.page | 65 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2015-08-18 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 分子與細胞生物學研究所 | zh_TW |
| 顯示於系所單位： | 分子與細胞生物學研究所 | |
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