LRWD1(Leucine-Rich repeats and WD repeat domain containing 1)基因在先前研究中發現表現量在造精功能障礙患者睪丸組織中較低。LRWD1在真核生物中擁有高度的保守性。在睪丸細胞株暴露在氧化壓力的環境中會使LRWD1的mRNA和蛋白質表現增加。同時，斑馬魚的LRWD1被報導在胚胎早期就有表現。在脊椎動物早期胚胎發育中，ROS的清除是必須的。LRWD1也被報導受到NRF2在轉錄上的調控，而NRF2會受到ROS調控。並且經本實驗室發現在lrwd1缺失的時候，ROS會上升，此結果推測lrwd1可能參與在ROS(Reactive oxygen species)的清除。本研究發現lrwd1基因在斑馬魚早期胚胎有不同mRNA同種型(isoform)的存在，包含通過不同的轉錄起始位點(transcript variant)或者通過選擇性剪接(alternative splicing)而產生。利用之前學長使用TALEN技術建立的lrwd1點突變魚分析ago2和fxr1兩個氧化壓力指標的基因表現，發現基因表現有顯著上升，表明ROS有累積的現象。但是在lrwd1點突變魚品系當中發現在不同世代的生理缺陷有減輕的現象，並且根據先前報導基因突變可能會產生補償作用。因此為了避免基因補償作用，經由morpholino抑制和CRISPR/Cas9系統進行啟動子剔除，兩者皆發現lrwd1缺失的時候胚胎出現ROS的累積和體軸發育缺陷。而lrwd1的過度表現同樣發現胚胎出現ROS的累積。本實驗結果推測lrwd1基因對於斑馬魚早期胚胎發育的ROS的清除扮演重要的功能。

From the previous studies, LRWD1(Leucine-Rich repeats and WD repeat domain containing 1) was first found as one of the significantly down-regulated genes in the testicular tissues of patients with spermatogenic defect. LRWD1 is highly conserved in vertebrates. A significantly increased level of LRWD1 mRNA and protein when exposure to hydrogen peroxide (H2O2) in NT2/D1 cell. At the same time, Lrwd1 had been reported to be expressed in the early zebrafish embryo. In the early embryonic development of vertebrates, there is important for the elimination of ROS. The temporal pattern of ROS level is similar to the expression of lrwd1 in zebrafish early embryonic development. Lrwd1 also had been reported to be transcriptionally regulated by Nrf2, and Nrf2 is regulated by ROS. In our lab, we found lrwd1 mutant embryo show the accumulation of ROS. We suggested that lrwd1 may be in charge of ROS clearance during the zebrafish early embryonic development. According to the NCBI database and our study, there were different lrwd1 isoforms can be detected during zebrafish early embryonic development. It includes 3 transcription variants and at least 2 alternative splicing isoforms. We also found up-regulated expression of ago2 and fxr1 as the ROS marker in the lrwd1 knockout embryo. However, phenotypic defects were reduced among generations in point mutant fish line, suggesting it may contain genetic compensation according to previous reports. Therefore, in order to avoid gene compensation, the morpholino knockdown and promoter-less mutant generated by CRISPR/Cas9 system were used to study the loss-of-function defect. Both results showed that embryos had ROS accumulation and tail trunction. Besides, the overexpression of lrwd1 also resulted in the accumulation of ROS in embryos. The results of this experiment speculate that the lrwd1 gene plays an important role in the elimination of ROS during early embryonic development of zebrafish.

戴季平，利用斑馬魚系統探討LRWD1基因所扮演的角色，國立台南大學生物科技學系碩士論文，2014。

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