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研究生:劉兆蓮
研究生(外文):Chao-Lien Liu
論文名稱:基因轉殖動物模式研究人類L2DTL基因
論文名稱(外文):Transgenic mouse models for the study of human L2DTL gene
指導教授:許輝吉許輝吉引用關係
指導教授(外文):Hey-Chi Hsu
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:病理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
畢業學年度:95
語文別:英文
論文頁數:85
中文關鍵詞:發育死亡核酸干擾細胞分裂
外文關鍵詞:L2dtldevelopmentlethalsiRNA knockdowncell division
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人類L2DTL基因是因與果蠅(Drosophila melanogaster)的致命性基因lethal (2) denticleless,簡稱l(2)dtl,相似而命名。果蠅之l(2)dtl 基因是因果蠅若發生該基因之同型合子突變(homozygous mutations),其胚胎會死亡(lethal),且缺失腹部齒狀帶(ventral denticle belts),而得名。最近的研究發現該基因蛋白是核蛋白,與核基質相連,表現於胚胎癌細胞株NT2,但在retinoic acid誘發分化時,則發生調降現象,故著者稱之為ramp蛋白。本研究室發現L2DTL mRNA表現在大多數人類胚胎組織發育,包括肝臟。而在單一原發性肝癌中,我們發現肝癌有L2DTL mRNA的過度表現,此種過度表現伴隨大顆粒、分級高及分期高之較惡性腫瘤。我們的觀察顯示L2DTL在cytokinesis與細胞增生伴有重要角色。在肝癌及一些常見癌症的過度表現也顯示L2DTL在癌症的發生上可能的重要性,也是一急待開發的領域。另外,在核酸序列與蛋白序列的分析中發現果蠅、老鼠與人類的重要序列很相似。我們也利用RT-PCR方法,發現L2dtl表現在鼠胚E0~E12.5及成鼠的高度分化器官,如:胸腺、脾臟及睪丸。我們利用基因剔除小鼠模式來研究L2dtl在胚胎發育上扮演何種功能,在基因剔除小鼠的結果中發現L2dtl-/-在胚胎發育的早期即致死,其表現型為胚胎無法發育且死於4到8個細胞之間。 微量注射L2dtl的核酸干擾載體 (siRNA-L2dtl)進入兩顆細胞時期的鼠胚細胞核中,也發現L2dtl基因被干擾後胚胎的細胞週期失敗,致細胞無法分裂而導致胚胎死亡在著床前期 (pre-implantation stage),以形態學分析胚胎受干擾的第54個小時出現分裂的染色體斷裂 (fragmentation of mitotic chromosome)及延遲 (chromosomal lagging)像似核分裂的大變動 (mitotic catastrophe)。在體外培養72個小時後,L2dtl核酸干擾的胚即崩解而無法發育至囊胚期 (blastocysts),但是如果是注射L2dtl核酸干擾進入兩顆細胞期胚的其中一顆細胞核,則其發育即不受影響。核酸干擾研究在HeLa細胞株時發現,L2dtl受干擾導致細胞出現多核現象 (multi-nucleation),使得PI3K、 PCNA及PTTG1/Securin表現下降此現象可大概解釋鼠胚中L2dtl受干擾所致的核分裂的大變動。借由這些發現,我們可以說L2dtl對老鼠胚胎的早期發育是相當重要的。
在此研究中,我們利用基因轉殖方式建立L2DTL基因過表現型鼠(gene over-expressed transgenic mice)與L2dtl基因剔除鼠(L2dtl knock-out mice),以期瞭解L2DTL基因在癌化過程(tumorigenesis)及胚胎發育過程(embryonic development)所扮演的重要性為何,以下為本研究的結論。

L2DTL基因過表現型小鼠部份:
(1). 以肝細胞專一性的前導子(promoter)建立人類L2DTL基因過表現型小鼠,自然情況下無法產生肝癌。
(2). 分析轉殖小鼠的表現型,利用三分之二肝臟切除及免疫組織化學染色法分析得知,L2DTL基因確實具有促使肝細胞分化與再生之能力。

L2dtl基因剔除鼠部份:
(1). 老鼠L2dtl基因在核酸及蛋白序列都與人和果蠅很相近其高度表現於E0-E12.5的胚胎及成鼠的高度分化器官,如: 胸腺, 脾臟及睪丸。
(2). 基因剔除鼠的表現形如其在果蠅觀察到的現象為胚胎早期致死。
(3). 經由顯微注射核酸干擾入老鼠胚胎的結果證實,胚胎受核酸干擾後會導致核分裂的大變動而無法正常分裂。
(4). 再由人類HeLa細胞株中的L2DTL核酸干擾結果,得知L2DTL的調降同時也導致PI3K、 PCNA 及PTTG1/Securin基因的調降。

綜合以上結果可知,L2DTL基因確實在DNA複製時扮演重要的角色,我們雖然無法在自然情況下看到L2DTL基因過表現小鼠產生肝癌,但在三分之二肝臟切除手術中確知其再生能力增加,顯示L2DTL基因確實與細胞的增生(proliferation)相關,而在L2dtl基因剔除鼠中發現胚胎發育到4-8顆細胞時即致死,且其核分裂的大變動是因受細胞週期調控中參與DNA複製的PI3K、PCNA基因及參與染色體分裂的PTTG1/Securin基因也同時被調降所致。
Lethal (2) denticleless (l(2)dtl), initially identified in Drosophila melanogaster, was so designated because the embryonic lethal homozygous mutation resulted in embryos that lacked ventral denticle belts. L2DTL protein is a nuclear matrix-associated protein and is downregulated during RA-induced neuronal differentiation of NT2 cells, designated as ramp (retinoid acid-regulated nuclear matrix-associated protein). We showed that L2DTL mRNA was expressed in multiple fetal tissues, including liver. L2DTL is over-expressed in unifocal primary HCCs. L2DTL overexpression correlated with larger tumor, higher-grade, and higher-stage malignant tumors. Our observations indicate that L2DTL plays an important role in the cytokinesis, cell proliferation and even in the tumorigenesis and tumor progression of HCC and other cancers. In addition to nucleotide sequence, bioinformatics analysis reveals conservation of critical functional motifs among the human L2DTL, mouse L2dtl and Drosophila l(2)dtl proteins. We studied the function of L2tdl in the development of mammalian embryos using a targeted disruption of the L2dtl gene in mice. The L2tdl knockout resulted in early embryonic lethality. L2dtl -/- embryos were deformed and development was terminated at the 4- to 8-cell stage. We then did siRNA knockdown of L2dtl using intranuclear microinjection of siRNA vector (siRNA-L2dtl) into the 2-cell stage nuclei of wild-type mouse embryos. The L2dtl knockdown caused failure of cell cycle progression, termination of cell division and eventually embryonic death at the pre-implantation stage. Morphological studies of the embryos 54 hours after injection showed fragmentation of mitotic chromosomes and chromosomal lagging, the features of mitotic catastrophe. The siRNA-L2dtl treated embryos eventually lysed, and failed to develop into blastocysts after 72 hours of in vitro culturing. In contrast, the embryos developed normally when microinjected into one nucleus of the two-cell embryos. The siRNA studies in HeLa cells showed that L2DTL depletion resulted in multi-nucleation, and down-regulation of PI3K, PCNA and PTTG1/Securin, which might partly explain the mitotic catastrophe observed in the L2dtl depleted mouse embryo. Based on these findings, we conclude that L2dtl is crucial for cell division and essential for very early mouse embryonic development.

However, in this study, we used the human L2DTL transgenic mice and L2dtl knock-out mice to verify the importance of L2DTL gene in tumorigenesis and embryogenesis, the summary of the results showed

The section of human L2DTL transgenic mice:
(1). No spontaneous development of hepatic tumors in transgenic mice with liver-specific over-expression of human L2DTL.
(2). Accelerated hepatic proliferation (regeneration) was observed in L2DTL transgenic mice after partial hepatectomy, compared to the wild type littermate.

The section of L2dtl knock-out mice:
(1). The nucleotide and amino-acid sequences of mouse L2dtl were highly conserved with human-L2DTL and Drosophila l(2)dtl. Mouse L2dtl were up-regulated in the E0-E12.5 and the adult highly proliferate organs: thymus, spleen and testis.
(2). L2dtl knock-out was embryonic lethality at the early pre-implantation stage in its phenotype.
(3). As the results of the microinjection of L2dtl-siRNA vector into two-celled stage embryos, the embryos can not growth normally due to mitotic catastrophe.
(4). By the human L2DTL siRNA knockdown in HeLa cells showed that L2DTL depletion resulted in down-regulation of PI3K, PCNA and PTTG1/Securin genes.

Our studies demonstrated for the first time the role of L2DTL gene in the proliferation (regeneration) of hepatic cells. Further studies are needed to elucidate the roles of L2DTL in hepatic tumorigenesis. Besides, L2DTL really play an important role in DNA replication that caused the L2dtl knock-out phenotype which was early embryonic lethality at 4-8 cells stage. The knockdown embryos result in mitotic catastrophe was caused by the down-regulation of the involved in DNA replication and chromosome segregation genes PI3K, PCNA and PTTG1/Securin.
Preface …………………………………………………….. II
前言 …………………………………………………….. IV
致謝 …………………………………………………….. VI
Abbreviation …………………………………………………….. VII
Outline …………………………………………………….. VIII

中文摘要 ……………………………………………………. 1
Abstract in English …………………………………………………..... 3

1. Introduction
1.1 The molecular etiologies of hepatocellular carcinoma …………….. 5
1.2 Cloning of L2DTL and bioinformatics analysis of L2DTL, L2dtl
and l(2)dtl …………………………………………………………... 5
1.3 Expression of human L2DTL in fetal and adult tissues and the clinicopathological siginificance in hepatocellular carcinoma ……... 6
1.4 First step to elucidate the L2dtl knockout phenotype ………………... 7
1.5 Transgenic mouse model for the study of human L2DTL’s function
in HCC ……………………………………………………………...... 7
1.6 Liver regeneration assay and the genes that regulation of cell-cycle in transgenic mice after 70% PHx ……………………………………... 8
1.7 Creation of the conditional knockout by using Cre/loxP system …...... 9

2. Materials and methods
Section I: L2DTL enhances liver regeneration after partial hepatectomy in transgenic mice
2.1 Overall strategy ………………………………………………….. 10
2.2 Construction of human L2DTL mini-gene driven by liver specific
Promoters ………………………………………………………….. 10
2.3 To verify the transgenic plasmids by transfection of cultured cells..... 11
2.4 Generation of L2DTL transgenic Mice, transgenic-lines breeding
and maintenance ………………………………………………….... 11
2.5 Analysis of human L2DTL mRNA in transgenic mice by RT-PCR .... 12
2.6 Liver cell proliferation assay of transgenic-lines by 70% PHx and
in vivo BrdUrd incorporation …………………………………….... 12

Section II: L2dtl is essential for cell survival and nuclear division in early mouse embryonic development
2.7 Strategies in this section ……………………………………………... 13
2.8 Screening and analysis of mouse BAC clones ……………………..... 14
2.9 Subcloning of DNA fragment containing exons 1-5 by gap repair ….. 14
2.10 Computer analysis of the mouse L2dtl gene ………………………... 15
2.11 Semi-Quantitative RT-PCR measurements ......................................... 15
Part A: L2dtl-conventional KO mice
2.12 Disruption of L2DTL in mouse embryonic stem cells …………...... 15
2.13 Southern blot analysis …………………………………………....... 16
2.14 Generation and genotyping of L2dtl deficient mice ……………..... 16
2.15 Timed pregnancies ……………………………………………….... 17
2.16 Genotyping of preimplantation stage embryos …………………..... 17
2.17 Construction of the siRNA expression vector …………………....... 18
2.18 Embryo collection, microinjection and culture for siRNA analysis.... 18
2.19 Semi-Quantitative RT-PCR ……………………………………..... 19
2.20 Western blot analysis …………………………………………….. 19
2.21 Nuclear morphology of embryos ……………………………….... 19
2.22 RNAi knockdown of L2dtl and multi-nucleated cell detection HeLa
cells ………………………………………………………………. 20
2.23 Antibodies ………………………………………………………... 20
2.24 Generation of anti-L2DTL antibodies ……………………………. 20
2.25 Statistical analysis ………………………………………………... 20
Part B: L2dtl-conditional KO mice
2.26 Construction of targeting vectors based on positive-negative selection
vector ………………………………………………………………. 21
2.27 Targeted disrupted of L2DTL gene in ES cell by homologous
recombination ……………………………………………………... 21
2.28 Identification of the correct ES clones by Southern blotting ……….. 21
2.29 In Vitro Excision of Floxed L2dtl in ES cells ……………………….. 22

3. Results
Section I: L2DTL enhances liver regeneration after partial hepatectomy in transgenic mice
3.1 Verification of the protein expression from the two transgenic constructs via transfection ………………………………………………………….... 23
3.2 L2DTL mRNA expression of the transgenic mice ………………….... 23
3.3 Liver regeneration rate after 70% PHx in the transgenic mice ……..... 24
Section II: L2dtl is essential for cell survival and nuclear division in early mouse embryonic development
3.4 Screening and analysis of mouse BAC clones ………………………. 24
3.5 Subcloning of DNA fragment containing exons 1-5 by gap repair…... 24
3.6 L2dtl genomic structure and amino acid sequence analysis …………. 25
3.7 L2dtl is expressed in mouse embryos and highly proliferative postnatal
organs ……………………………………………………………….... 26
Part A: L2dtl-conventional KO mice
3.8 Generation and characterization of L2dtl knock-out mice ………….... 26
3.9 In vitro analysis of early embryos ……………………………………... 27
3.10 Phenotypic analysis of L2dtl-null embryos by nuclear microinjection
of siRNA-vector …………………………………………………….... 27
3.11 Reduction of human L2DTL expression by RNAi oligos leads to increase
in the population of multi-nucleated cells in HeLa cells …………….. 28
Part B: L2dtl-conditional KO mice
3.12 Generation of L2dtl conditional knock-out mice …………………….. 28
3.13 Deletion of Exon 2 and 3 in ES cells by “Cre recombinase”…………. 29

4. Discussions
Section I: L2DTL enhances liver regeneration after partial hepatectomy in transgenic mice
4.1 Applications of transgenic mouse technology ………………………….. 30
4.2 Designing Transgenes …………………………………………………... 31
4.3 Establishment and maintenance of transgenic mouse lines …………….. 33
4.4 Differential cell and tissue expressions of human L2DTL transgene in
mice ……………………………………………………………… 34
4.5 L2DTL-Tg mice exhibits enhanced cell proliferation and liver
Regeneration ……………………………………………………… 34
4.6 Summary of this section ……………………………………………….... 35
Section II: L2dtl is essential for cell survival and nuclear division in early mouse embryonic development
4.7 The advantages of the highly efficient λ-phage recombination system… 36
4.8 Interspecies comparisons of human L2DTL, mouse L2dtl and Drosophila
l(2)dtl …………………………………………………………………… 36
Part A: The conventional knock-out mice
4.9 Characterization and analysis of the phenotypes of conventional knock-out
mice …………………………………………………………………… 37
4.10 The mechanistic understanding of L2DTL in relationship to the observed
phenotype by SiRNA knockdown assays ……………………………... 38
Part B: The conditional knock-out mice.
4.11 Generation of L2dtl Exon 2 and 3 in-frame deletion conditional knock-out
mice …………………………………………………………………… 40
5. Figures
Section I: L2DTL enhances liver regeneration after partial hepatectomy in
transgenic mice
Figure 1: The pAlb.polyA vector used for constructing the transgenic plasmid … 42
Figure 2: The pBS-HCRI-A vector used for constructing the transgenic plasmid..... 43
Figure 3: Two of the L2DTL-Tg linear targeting vectors with liver specific
promoters……………………………………………………………... 44
Figure 4: Verification of L2DTL protein expression of each transgenic construction
by hepatoma cell line “Huh-7” transfection …………………………. 45
Figure 5: Verification of L2DTL protein expression of each transgenic construction in
transfected cervical cancer cell line “HeLa”…………………………. 46
Figure 6: Generation of L2DTL transgenic mice by microinjection with
pBS-Flag-L2DTL-I2 transgenic construct …………………………… 47
Figure 7: Generation of L2DTL transgenic mice by microinjection with
Alb-Flag-L2DTL-I2 transgenic construct ……………………………. 48
Figure 8: Detection of the L2dtl RNA expression level in each transgenic lines by
quantitative RT-PCR analysis ………………………………………... 49
Figure 9: Expression of human L2DTL mRNA in transgenic lines …………….. 50
Figure 10: Gene expression during the priming phase of liver regeneration after partial
hepatectomy in mice …………………………………………………. 51
Figure 11: Phenotypes in transgenic mice receiving 70% PHx ………………… 52
Figure 12: Increase in BrdUrd incorporation in regenerating livers of L2DTL
transgenic mice 48 h after 70% PHx …………………………………. 53
Figure 13: The induction of liver tumor by chemical carcinogens in human L2DTL
transgenic mice ………………………………………………………. 54
Section II: L2dtl is essential for cell survival and nuclear division in early mouse
embryonic development
Figure 14: Genomic DNA inserted with BAC clones ……………………………. 55
Figure 15: Subcloning of exon 1 to 5 of L2dtl from BAC clone by gap repair ….. 56
Figure 16: Genomic structure of mouse L2dtl and phylogenetic comparison of the
primary structure with Drosophila l(2)dtl and human L2DTL ……….. 57
Figure 17: Expression profile of L2dtl mRNA in mouse embryos and tissues….... 58
Figure 18: Generation of L2dtl knockout mice………………………………….... 59
Figure 19: Conventional L2dtl knockout embryos at different gestation stage…... 60
Figure 20: Loss of L2dtl causes early termination of development in L2dtl-/-
Embryos …………………………………………………………….... 61
Figure 21: L2dtl siRNA knockdown markedly decreases L2dtl expression and
blocks embryonic development …………………………………….... 62
Figure 22: L2dtl siRNA knockdown can not function when microinjected into one
nucleus of the two-celled embryo due to the cell autonomous manner.........63
Figure 23: The phenotype and nuclear morphology of blastocysts 72 hours after the
nuclear injection of different vectors into two-cell stage embryos……….. 64
Figure 24: Suppression of L2DTL expression by RNAi oligos raised the
multi-nucleated events in HeLa cells …………………………………... 65
Figure 25: Generation of L2dtl conditional knockout mice ……………………... 66
Figure 26: Generation of two types of ES clones by Cre recombinase ………...... 67
6. Tables
Section I: L2DTL enhances liver regeneration after partial hepatectomy in
transgenic mice
Table 1: The number of transgenic and wild-type litters (Tg/Wt) mice after partial
hepatectomy (PHx) at each time point ………………………………… 68
Section II: L2dtl is essential for cell survival and nuclear division in early mouse
embryonic development
Table 2: The sequence of gap-repair primers and each conformed L2dtl exons primer
pairs ……………………………………………………………………. 69
Table 3: Genotyping of progenies from heterozygous matings ……………….... 70
Table 4: In vitro development effects of L2dtl siRNA knockdown via injection of one
and two nuclei of two-cell stage mouse embryos ……………………... 71
7. Refferences ………………………………………………………….............. 72
8. Submitted and corrected papers …………………………………………... 85
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