臺灣博碩士論文加值系統

果蠅胚胎背腹極性的建立，主要是由位於胚胎腹側的Toll−Dorsal訊息傳遞所控制。在先前的研究中，已找出15個參與這個訊息傳遞過程的基因，統稱背部基因群（dorsal group genes）；目前認為這些背部基因群的基因是以直線方式來傳遞訊息的。當Toll的胞外功能區(extracellular domain)與活化的ligand spätzle結合而具有活性時，它的胞內功能區(intracellular domain)會結合DmMyD88，並透過DmMyD88再結合Tube，然後將訊息傳至Pelle，最後導致Cactus水解，使轉錄因子(transcription factor) Dorsal/Dif能夠進入細胞核內，並調節下游基因的表現。Weckle (wek)是之前被找到的一個新的背部基因群的基因，它是一個帶有6個zinc-finger domain的轉錄因子，然而它在Toll pathway 中所扮演的角色仍不清楚。
本論文敘述經分離出新的wek果蠅突變株，由遺傳上位測試（genetic epistatic analysis）的結果得知wek位於Toll的下游、cactus的上游。雖然Wek是一個帶有zinc-finger的蛋白，然而在胚胎的免疫染色中，我們卻發現它位於細胞膜上，而且不需要有Toll的訊息。從蛋白質的結合測試，得知，Wek會形成dimer且會與Toll receptor及DmMyD88結合，將DmMyD88帶到細胞膜上；這充分印證了先前的染色結果。因此我們認為，Wek在果蠅胚胎時期，在Toll 訊號傳遞中的作用主要是聚集並穩固Toll/DmMyD88/Tube/Pelle所形成的訊息複合體，幫助訊號的傳遞。
果蠅的Toll−Dorsal pathway除了參與果蠅胚胎背腹極性的建立外亦參與成蟲的免疫反應。但在我們免疫染色的結果中卻發現不同於果蠅胚胎，在果蠅fat body的細胞中Wek主要表現於細胞核內。而在其他的實驗結果也證實，Wek在果蠅的免疫反應中-在對抗葛蘭氏陽性菌或黴菌的感染上並不扮演重要角色。

The Toll-Dorsal pathway was identified to participate in dorsoventral axis formation of Drosophila embryo. Previous screenings had identified 15 dorsal group genes that were arranged in a linear pathway. Toll is activated by the binding of its ligand Spätzle. Upon Toll activation, it interacts with the adaptor proteins DmMyD88, Tube and the kinase Pelle, and triggers degradation of the inhibitor Cactus, thus allowing the nuclear translocation of the transcription factor Dorsal/Dif. weckle (wek) was previously identified as a new dorsal group gene that encodes a putative zinc-finger transcription factor. However, its role in Toll pathway was unknown.
Here, we isolated new wek alleles and demonstrated that wek acts upstream of cactus but downstream of Toll. Although wek encodes a zinc-finger protein, it localizes to the plasma membrane of embryos, independent of Toll signaling. Wek forms homodimer and associates with Toll. Moreover, Wek binds to DmMyD88 and localizes it to the plasma membrane. Thus, Wek acts as an adaptor to assemble/stabilize a Toll/Wek/DmMyD88/Tube complex.
The Toll pathway was also identified to involve in the innate immune response of adult fly. However, different from the membrane localization of embryos, Wek localized to the nucleus of fat body cells. Unlike the DmMyD88/tube/pelle/cactus gene cassette of the Toll pathway in embryo, wek plays a minimal role in the immune defense against Gram-positive bacteria and fungi.

Publication list i
Abbreviations ii
中文摘要 iii
Abstract v

Chapter 1 General introduction
Dorsoventral axis formation in the Drosophila embryo 2
The early ventralising information in ventral perivitelline fluid 5
The Toll pathway 8
Drosophila innate immune response 11
Cellular response: blood cells 11
Humoral response: antimicrobial peptides and two regulatory pathways 12
Figures and Table 16
Chapter 2 Weckle is a new component of the Toll pathway in dorsoventral patterning of the Drosophila embryo
Introduction 23
Materials and methods 25
Results 28
Discussion 36
Figures and Table 40
Chapter 3 Identify Weckle function in Drosophila innate immune response
Introduction 55
Materials and methods 56
Results 58
Discussion 59
Figure 63
Reference 64
Appendix (These works were contributed by cooperator) 73

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