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研究生:林盈宏
研究生(外文):Ying-hung Lin
論文名稱:探討Septin12基因參與哺乳動物精子發育之功能
論文名稱(外文):Identification and characterization of Septin12 gene in mammalian spermatogenesis
指導教授:郭保麟郭保麟引用關係
指導教授(外文):Pao-lin Kuo
學位類別:博士
校院名稱:國立成功大學
系所名稱:基礎醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:83
中文關鍵詞:精子生成不孕症
外文關鍵詞:spermatogenesisinfertility
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已婚夫婦中約有10-15﹪的夫妻有不孕症的困擾,其中約有一半是男性因素所造成。 至今仍有25%男性不孕症病患,病因仍不清楚。 近年來於果蠅及老鼠動物模式中,發現許多基因會影響其生殖能力,顯示出遺傳因素可能於物種的不孕有很大的影響,但這些基因在精子發育過程之中的角色,卻只有少數被瞭解。 本研究主要在尋找參與精子發育過程的新穎基因並鑑定其功能。 我們藉由cDNA微陣列晶片,分析不孕症男性與健康男性睪丸中基因表現的差異,經統計分析後得到十個於造精功能障礙較正常睪丸組織間表現量下降之新穎基因,本論文研究的重點是針對其中一個專一表現於睪丸的Septin12基因(SEPT12)進行探討。
SEPT家族屬於具有GTP結合能力的細胞骨架蛋白且參與細胞區室化,曩泡運輸, 細胞分裂與細胞骨架重整。 Septin12基因特異表現於人類與小鼠睪丸組織。 於精子生成過程,SEPT12表現於精子頂體外圍,頸部與精子中節和尾部交接的環狀結構。 於Septin12基因剔除嵌合公鼠為不孕且睪丸重量明顯下降。 於精液分析發現,精子數目,活動力與正常型態精子數目明顯減少。 於嵌合小鼠睪丸切片發現生精作用一致性下降或停置於圓形精細胞階段,並伴隨精細胞凋亡情形增加。 於嵌合小鼠精子同時具有精細胞頂體部破損與尾部彎曲情形。 經由穿透式電子顯微鏡分析也發現鑲嵌小鼠精子頂體部外膜受損,粒線體減少與排列不完整和細胞核有空泡產生。 另於男性不孕症患者睪丸組織中,SEPTIN12 mRNA含量下降。 利用螢光免疫染色發現,精子無力症與精子型態異常的病患,SEPT12表現量有明顯下降的情形。 總括本研究結果證實,SEPT12於哺乳類精子生成與男性不孕症扮演重要的角色。
It is estimated that 10- 15% of couples are infertile and male factors account for about half of the cases. About 25% of the causes of male infertility are still unknown and the majority of infertile cases have defects in spermatogenesis. But large of those spermatogenesis are still unknown. To identify novel genes which are involved in mammalian spermatogenesis, we studied global gene expression patterns in testicular biopsies of men with spermatogenic defects by c-DNA microarrays. We found ten novel genes of which transcripts were significantly decreased in patients with Sertoli cell only syndrome or Maturation arrest. Because the transcripts of Septin12 (SEPT12) are specific express in human and mouse testis. We chose Septin12 gene for further study.
Septins belong to a family of polymerizing GTP binding proteins that are required for many cellular functions, including membrane compartmentalization, vesicle trafficking, mitosis and cytoskeletal remodeling. In this study, we found SEPTIN12, one of the SEPTIN family members, is expressed specifically in the testis. SEPT12 expressed in multiple subcellular compartments during terminal differentiation of post-meiotic germ cells. To elucidate the role of Septin12, we generated 129 ES cells with a Septin12 mutant allele deleted in the exons encoding the N-terminal GTP binding domain. Most chimeras derived from the targeted ES cells were infertile. Semen analysis of the infertile chimeras showed decreased sperm counts, decreased sperm motility, and spermatozoa with defects involving all subcellular compartments. The testicular phenotypes included maturation arrest of germ cells at the spermatid stage, sloughing of round spermatids and increased apoptosis of germ cells. Electron microscopic examination of spermatozoa showed misshapen nuclei, disorganized mitochondria and broken acrosome. In humans, the testicular tissues of men with hypo-spermatogenesis or maturation arrest had lower levels of the SEPTIN12 transcripts. In addition, more spermatozoa with abnormal head, neck and tail morphology lacked SEPT12 immunostaining signals compared to spermatozoa with normal appearance. Our data support a critical role of Septin12 during mammalian spermiogenesis.
Abstract in Chinese ----------------------------------------------------------------------------1
Abstract------------------------------------------------------------------------------------------2
Acknowledgements-----------------------------------------------------------------------------4
I. Literature Review----------------------------------------------------------------------------5
1.1 Male infertility and Spermatogenesis -----------------------------------------------5
1.2 Identification of sterility-related genes during mammalian spermatogenesis--6
1.3 The functional roles of Septin from yeasts to human -------------------------6
1.4 The reproductive roles of SEPTs in model organisms ----------------------------8
1.5 Septins and diseases--------------------------------------------------------------------9
1.6 Goals of this work --------------------------------------------------------------------9
II. Materials and Methods-------------------------------------------------------------------11
2.1 Patients----------------------------------------------------------------------------------11
2.2 Testicular tissues-----------------------------------------------------------------------12
2.3 Microarray analysis-------------------------------------------------------------------12
2.4 Novel genes and similarity search---------------------------------------------------13
2.5 Semi-quantitative Reverse Transcription (RT)-PCR------------------------------13
2.6 RT-PCR for expression patterns of novel genes and Septin12-------------------14
2.7 5’ and 3’ Rapid Amplification of cDNA Ends (RACE), genomic database search and sequence alignment --------------------------------------------------15
2.8 Plasmid construction, cell culture, transfection and immunofluorescence ----15
2.9 Separation of the testicular germ cell populations and sperm preparation-----16
2.10 Generation of anti-SEPT12, western blot analysis and immuno fluorescence study-----------------------------------------------------------------------------------17
2.11 Targeting vector and generation of mutant Mice--------------------------------18
2.12 Semen analysis and TUNEL assay------------------------------------------------18
2.13 Electron microscopy----------------------------------------------------------------19
III Results---------------------------------------------------------------------------------------21
3.1 Down-regulated genes in the testicular tissue with spermatogenic defects ---21
3.2 Validation of microarray data for novel genes-------------------------------------21
3.3 Genomic structure and functional domains of novel genes----------------------22
3.4 Expression pattern of novel genes in micee and human-------------------------22
3.5 Developmental stage-dependent expressions of novel genes in mouse testes-23
3.6 Identification of full length Septin12 transcripts by RACE in mammalian --23
3.7 Septin12 is expressesed in the post-meiotic germ cells --------------------------24
3.8 Reproductive phenotypes of the Septin12+/- chimera mice-----------------------25
3.9 Sperm acrosome and tail defects in Septin12+/- chimera mice-------------------26
3.10 Ultrastructural abnormalities of spermatozoa in the Septin12+/- chimeric mice ------------------------------------------------------------------------------------------27
3.11 Dis-origanized annulus/SEPT rings of spermatozoa in the Septin12 ko chimeric mice -------------------------------------------------------------------28
3.12 Altered expression pattern of SEPT12 in human spermatozoa with abnormal morphology---------------------------------------------------------------------------28
IV. Discussions---------------------------------------------------------------------------------30
4.1 Microarrray analysis of the mammalian testis ------------------------------------30
4.2 Testis-enriched genes which when maturated, may be involved in
spermatogenic defect-----------------------------------------------------31
4.3 The functional role of novel sterility-related genes ------------------------------31
4.4 SEPTs in mammalian spermatogenesis --------------------------------------------34
4.5 SEPT 1/4/6/7 complexs and SEPT12 in mouse spermatogenesis---------------34
4.6 SEPTs and microtubulins ------------------------------------------------------------35
4.7 Haploinsufficiency of SEPT12 during spermatogenesis ------------------------36
4.8 The roles of SEPT12 in male infertility --------------------------------------------38
4.9 Characterization of Septin12 gene in mammalian spermiogenesis -------39
VI. References----------------------------------------------------------------------------------41


List of Figures
Figure 1. Microarray analysis of the human testicular tissue-----------------------------55
Figure 2. Semi-quantitative RT-PCR analysis for 5 novel genes which are down- regulated in Sertoli cell only syndrome (SCOS) ------------------------------56
Figure 3. Semi-quantitative RT-PCR analysis for 8 novel genes which are down-regulated in maturation arrest (MA) -------------------------------------57
Figure 4. The genomic structure, functional domains, size of human transcript, total number of amino acids, and chromosomal localization of novel sterile genes ----------------------------------------------------------------------------------------58
Figure 5. RT-PCR analysis for expression of novel sterile genes in different human (A) and mouse organs (B) -------------------------------------------------------------59
Figure 6. Developmentally regulated expression of mouse orthologues----------------60
Figure 7 Schematic presentations of major Septin12 transcripts in mice and human-61
Figure 8 RT-PCR expression profiles of Septin12 in humans and mice ----------------63
Figure 9 Over-expression of Seprin12 form filaments-like structures in 293T cells -64
Figure 10 Expression pattern and localization of the SEPT12 protein -----------------65
Figure 11 Targeted disruption of Septin12 causes male fertility ------------------------66
Figure 12 The reproductive phenotypes of chimeras (I) ---------------------------------68
Figure 13. The reproductive phenotypes of chimeras (II) -------------------------------70
Figure 14. Electron microscopy shows defects in sperm acrosome and mitochondrial architecture in the chimeric mice -----------------------------------------------71
Figure 15. Dis-localization of SEPT7 in Septin12 Ko chimeric mice sperm ---------72
Figure 16. The expression of SEPTIN12 decreases in infertile men --------------------73
Figure 17. Decreased expression level of SEPT12 in spermatozoa with abnormal morphology -------------------------------------------------------------------------74
Figure18. A working model of SEPT12 during spermiogenesis-------------------------75












List of Tables
Table1. The number of genes which are significantly down-regulated in the testicular samples ------------------------------------------------------------------------------76
Table2. List of testis-enriched genes --------------------------------------------------------77
Table3. List of novel genes -------------------------------------------------------------------78
Table4. List of novel genes primer sequences for RT-PCR ------------------------------79
Table5. List of Septin12 specific primer sequences for RACE and Real-time RT
-PCR-------------------------------------------------------------------------------------80
Table6. The percentages of abnormal spermatozoa from the cauda epidydimis of mice ------------------------------------------------------------------------------------------81
Publications----------------------------------------------------------------------82
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