臺灣博碩士論文加值系統

在神神經發育過程中,由於綜合了了位置上與時機上的調控,而確定了了哪些細胞具有 形成神神經細胞的潛力力。感受外界訊號的果蠅感覺器官剛毛可以接受機械性及化學 性的刺刺激,並排列列整齊。在翅膀前緣,有神神經連連結的剛毛整齊排列列,而在翅膀後 緣則是排列列著無神神經連連結的剛毛。我們發現在翅膀後緣,COP9 複雜亞單位 (CSN) 抑制了了神神經細胞潛力力而使得最終形成無神神經剛毛。在 CSN 的突變中,翅膀後緣 的剛毛細胞會因為神神經決定因子— Senseless (Sens)的持續表達,而轉變成為有神神 經連連結的剛毛。CSN 抑制 Sens 的功能是透過抑制了了蛻皮激素訊號傳遞鏈的下游 基因 BR-Z1 轉錄錄因子的表達,而 BR-Z1 則會活化 Sens。特別的是,CSN 抑制 BR-Z1 的功能是從果蠅的前蛹時期轉變為蛹時期才開始,造成 Sens 在這時才開始下降降 並終止翅膀後緣神神經細胞的發育潛力力。而我們發現到,蛻皮激素訊號傳遞鏈在前 蛹時期轉變為蛹時期之後會抑制 br 表達,這和之前已知的蛻皮激素訊號傳遞鏈 會活化 br 的傳統調控相反。且這樣的抑制是需要 CSN deneddylation 的活性及其 目標蛋白--多種的 Cullin。而我們也發現到多個 CSN 子單位會和蛻皮激素的受體 (EcR)交互作用並且抑制 br 的轉錄錄。我們提出了了模型指出荷爾蒙受體 EcR 會和 CSN deneddylation 機轉共同作用,並適時的降降低其下游基因表達,確保在特定的 翅膀後緣區域抑制神神經細胞發育的潛力力。

During development, neural competence is conferred and maintained by integrating spatial and temporal regulations. The Drosophila sensory bristles that detect mechanical and chemical stimulations are arranged in stereotypical positions. The anterior wing margin (AWM) is arrayed with neuron-innervated sensory bristles while posterior wing margin (PWM) bristles are non-innervated. We found that the COP9 signalosome (CSN) suppresses the neural competence of non-innervated bristles at the PWM. In CSN mutants, PWM bristles are transformed into neuron-innervated, which is attributed to sustained expression of the neural-determining factor Senseless (Sens). The CSN suppresses Sens through repression of the ecdysone signaling target gene broad (br) that encodes the BR-Z1 transcription factor to activate sens expression. Strikingly, CSN suppression of BR-Z1 is initiated at the prepupa-to-pupa transition, leading to Sens downregulation, and termination of the neural competence of PWM bristles. The role of ecdysone signaling to repress br after the prepupa-to-pupa transition is distinct from its conventional role in activation, and requires CSN deneddylating activity and multiple cullins, the major substrates of deneddylation. Several CSN subunits physically associate with ecdysone receptors to represses br at the transcriptional level. We propose a model in which nuclear hormone receptors cooperate with the deneddylation machinery to temporally shutdown downstream target gene expression, conferring a spatial restriction on neural competence at the PWM.

Abbreviation ...................................................................................................................... III 中文摘要 ............................................................................................................................ IV
Abstract................................................................................................................................V
Introduction ..........................................................................................................................1
The external sensory organ in Drosophila...........................................................................1 The temporal ecdysone signaling ........................................................................................3 Ecdysone signaling and neural development .......................................................................4 The COP9 signalosome ......................................................................................................5 The COP9 signalosome on neural development and hormone signaling dependent transcriptional regulation ....................................................................................................6
Material and Methods ..........................................................................................................8
Fly strains and genetics.......................................................................................................8 Immunofluorescence staining ...........................................................................................10 Quantification of staining intensity ...................................................................................12 Cell culture and plasmid construction ...............................................................................12 S2 cells immunofluorescence staining...............................................................................13 Charcoal stripping of FBS and 20E treatment ...................................................................13 Co-immunoprecipitation ...................................................................................................13 Chromatin immunoprecipitation .......................................................................................14 RT-PCR............................................................................................................................14
Results .................................................................................................................................16
Bristle missing and cell fate transformation in CSN mutants .............................................16 Transformation of PWM bristles into innervated sensory bristles in CSN mutants.............17 The CSN suppresses Sens independent of proneural genes ac and sc ................................18 The CSN downregulates Engrailed in pupal wing discs.....................................................19 The CSN does not regulate apoptosis in wing tissues ........................................................20 Sens accumulation is induced by BR-Z1 upregulation in CSN mutant cells.......................20 CSN regulation of BR-Z1 and Sens levels is time-dependent ............................................21 Developmental program of AWM and PWM bristles in CSN mutants...............................23 Ecdysone receptor represses BR-Z1 after the prepupa-to-pupa transition ..........................23 CSN subunits associate with EcR to repress br transcription.............................................24
I
Nedd8 and multiple cullins are required to suppress BR-Z1 and Sens expressions ............26 Conclusion .......................................................................................................................27
Discussion............................................................................................................................28
Suppression of neural competence of non-innervated bristle at the PWM..........................28 Restricted neural formation at wing margin in CSN mutants .............................................30 ES organs on the notum and on the AWM ........................................................................30 Switch from activation to repression of ecdysone signaling target genes requires CSN deneddylation activity.......................................................................................................31 Multiple cullins that involved in br-Z1 inhibition..............................................................33 Possible candidates in the ecdysone dependent transition of CSN activity at pupal stage...33
References ...........................................................................................................................35 Figures and Figure Legends...............................................................................................46 Appendix.............................................................................................................................76

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