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研究生：	簡瑜 Chien, Yu
論文名稱：	研究造精過程中與細胞週期相關之基因 Characterization of cell-cycle related genes which may be critical for human spermatogenesis
指導教授：	郭保麟 Kuo, Pao-Lin
學位類別：	碩士 Master
系所名稱：	醫學院 - 生物化學暨分子生物學研究所 Department of Biochemistry and Molecular Biology
論文出版年：	2006
畢業學年度：	94
語文別：	英文
論文頁數：	79
中文關鍵詞：	造精過程、絲胺酸/酥胺酸激脢31 、細胞週期
外文關鍵詞：	cell cycle, KARCA1, STK31, spermatogenesis
相關次數：	點閱：133 下載：1
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世界上約有百分之二至十二比例的夫妻受到生殖能力降低的影響。男性及女性因素所導致的不孕約各佔百分之五十的比例。而大部分的不孕症男性通常在造精過程中有所缺陷。許多基因牽連在哺乳類的生殖過程中，而大多數仍未被探索。為了研究男性生殖過程，我們執行 cDNA 微陣列技術分析造精缺陷患者的睪丸組織。KARCA1 是被選擇進一步研究下降調節基因的其中之一。KARCA1 是一個包含 kelch/ankyrin重覆的 cyclin A1 交互作用蛋白。藉由酵母菌三重雜交方法，KARCA1 被發現在睪丸中為一新穎 cyclinA1/CDK2 交互作用蛋白。這暗示著 KARCA1 在生殖細胞減數分裂過程中扮演著調節的角色。微陣列技術的結果與即時反轉錄多重聚合酶鏈鎖反應的結果是一致的。KARCA1 的確在造精缺陷的病人當中是有意義的下降調節。我們發現 KARCA1 基因表現在人類及老鼠各種組織當中，以及藉由反轉錄多重聚合酶鏈鎖反應分析發現 KARCA1 從老鼠出生後第一天的睪丸表現至成鼠的睪丸。另一個與男性不孕症的候選研究基因為 STK31，只表現在老鼠的精原細胞。我們假設具有嚴重造精缺陷的病人具有生殖幹細胞或精原細胞的內生性缺陷。藉由即時反轉錄多重聚合酶鏈鎖反應分析，我們發現人類 STK31 確實在不具生殖細胞的病人睪丸組織當中是有意義的下降表現。我們也發現在整各造精過程當中也可以偵測到 STK31 轉錄子的存在。我們製造了 KARCA1 與 STK31 的多源性抗體。藉由執行西方墨點分析以及免疫化學組織染色來研究 KARCA1 與 STK31 蛋白的表現情形。KARCA1 蛋白在精原細胞、精母細胞以及精細胞的細胞質被偵測到。STK31 則表現在精原細胞與精母細胞。藉由GC-1 spg 細胞的免疫螢光染色分析， STK31 與 γ-tubulin 共同表現在紡錘體/中心體。許多細胞週期調節分子被發現位於中心體上。STK31 的激酶結構域與 BubR1 有演化上的保留性。因此我們假設 STK31 為生殖細胞專有的細胞週期檢查點的蛋白。

Between 2% and 12% of couples worldwide are affected by reduced fertility. Male factors and female factors accounts for approximately 50% of causes in infertile couples, respectively. In men, a large proportion of infertile men have defects in the process of spermatogenesis. Numerous genes are implicated in mammalian fertility pathways, the majority of which have not been explored. To study the male fertility pathways, we performed the cDNA microarray analysis of testicular tissues from patients with spermatogenic defect. KARCA1 was one of down-regulated genes chosen for further study. KARCA1 is a kelch/ankyrin repeat-containing cyclin A1-interacting protein. By the yeast triple-hybrid approach, KARCA1 was found to be a novel cyclinA1/CDK2 interaction partners in the testis. This suggests the regulatory role of KARCA1 during the meiotic division of germ cells. The result of microarray analysis was consistent with the real time RT-PCR. KARCA1 was significantly down-regulated in patients with spermatogenic defects. We found KARCA1 gene was expressed in various human and mouse tissues and its transcript was detectable from the testes of postnatal day1 to the adult mouse by RT-PCR analysis. The other candidate gene of male sterility was STK31, a gene expressed exclusively in the spermatogonia of mouse. We hypothesize that some cases with severe spermatogenic defect have intrinsic defect in germ-line stem cell or spermatogonia. By real-time RT-PCR analysis, we found that human STK31 was significantly decreased in the testicular tissue of patients without germ cells. We also found the transcript of mouse Stk31 was detectable throughout spermatogenesis. We generated polyclonal antibodies to KARCA1 and STK31. Western blot analysis and immunohistochemical staining were performed to study the expression pattern of KARCA1 and STK31. The KARCA1 protein was detectable in the cytoplasm of spermatogonia, spermatocytes and spermatid. IHC shows that Stk31 was expressed in spermatogonia and spermatocytes. By immunofliuorescence staining analysis of GC-1 spg cells with anti-STK31 and γ-tubulin, Stk31 was colocalized with γ-tubulin at the spindle pole/ centrosome. Many cell-cycle regulatory molecules are found at centrosomes. The kinase domain of STK31 has evolutionary conservation with BubR1. Therefore we hypothesize that STK31 is involved in cell-cycle checkpoint in a germ cell-specific manner.

Contents
Abstract in Chinese...........................................................1
Abstract in English...........................................................2
Acknowledgements..............................................................4
Contents......................................................................5
Contents of Figures and Appendix..............................................9
Abbreviation.................................................................11
1   INTRODUCTION.............................................................12
1.1	Pathogenesis of male infertility....................................12
1.2	Process of spermatogenesis..........................................12
1.2.1	Hormonal interaction Process of spermatogenesis.....................12
1.2.2    Spermatogenesis.....................................................13
1.3	Sterile genes.......................................................14
1.4	Cell-cycle releated genes involve in spermatogenesis................14
1.5	Candidate gene 1 – KARCA1..........................................16
1.6	Candidate gene 2 – STK31...........................................17
1.6.1	The pathological mechanism of spermatogenic defect..................17
1.6.2  Spermatogenia-specific genes are strong candidates of sterile genes...17
1.6.3  Studies on spermatogonia-specific genes and their therapeutic 
       implication...........................................................19
2   MATERIALS AND METHODS....................................................21
  2.1   Total RNA isolation..................................................21
    2.1.1   Materials........................................................21
    2.1.2   Method...........................................................21
  2.2   Reverse Transcription-Polymerase Chain Reaction, RT-PCR..............22
    2.2.1   Materials........................................................22
    2.2.2   Method...........................................................25
  2.3   Real-Time RT-PCR.....................................................26
    2.3.1   Materials........................................................26
    2.3.2   Method...........................................................27
  2.4   Statistical analysis.................................................28
    2.4.1   Materials........................................................28
    2.4.2   Method...........................................................28
  2.5   Antibody generation..................................................29
  2.6   SDS-polyacrylamide Gel Electrophoresis...............................30
    2.6.1   Materials........................................................30
    2.6.2   Method...........................................................31
  2.7  Western Blot..........................................................31
    2.7.1   Materials........................................................31
    2.7.2   Method...........................................................32
  2.8  Immunohistochemistry staining, IHC....................................33
  2.8.1   Materials..........................................................33
    2.8.2   Method...........................................................33
2.9  Culture and subculture GC-1 spg cells...................................36
  2.9.1   Materials..........................................................36
    2.9.2   Method...........................................................37
2.10  Cryopreservation of cultured cells.....................................37
  2.10.1  Materials..........................................................37
    2.10.2  Method...........................................................37
2.11  Immunofluorescence staining............................................38
  2.11.1  Materials..........................................................38
    2.11.2  Method...........................................................38
3   RESULT...................................................................40
  3.1   Down-regulation of KARCA1 and STK31 genes in infertile men...........40
  3.2   KARCA1 transcripts are most abundant in the human and mouse testes...40
  3.3   KARCA1 transcripts are expressed from the testes of postnatal day1 to 
        the adult in mouse...................................................40
  3.4   KARCA1 protein is expressed in spermatogonia, spermatocytes and 
        spermatid............................................................41
  3.5   STK31 transcripts are expressed from the testes of postnatal day1 to
        the adult mouse......................................................41
  3.6   STK31 are exclusively expressed in the human and mouse germ cells....42
  3.7   STK 31 was located at the centrosome of GC-1 spg cells...............42
4   DISCUSSION...............................................................43
  4.1   The role of KARCA1 in human reproduction.............................43
  4.2   STK31................................................................45
5   REFERENCES...............................................................49
Resume.......................................................................79

Contents of Figures and Appendix
Figure 1.  Real-time RT-PCR for KARCA1 in the human testes.                  59
Figure 2.  Real-time RT-PCR for STK31 in the human testes.                   60
Figure 3.  RT-PCR analysis of KARCA1 gene expression in multiple mouse tissues.                                                                     61
Figure 4.  RT-PCR analysis of KARAC1 gene expression in multiple human tissues.                                                                     62
Figure 5. Expression during of the KARCA1 gene during testicular development of mouse.                                                                    63
Figure 6.  Western Blot analysis of KARCA1.                                  64
Figure 7.  KARCA1 protein is expressed in spermatogonia, spermatocytes and 
           spermatid.                                  65                      
Figure 8. Expression of STK31 during testicular development of mouse.        66
Figure 9.  RT-PCR analysis of STK31 in multiple mouse tissues.               67
Figure 10.  RT-PCR analysis of STK31 in multiple human tissues.              68
Figure 11.  Western Blot analysis of STK31.                                  69
Figure 12.  STK31 protein is expressed in spermatogonia and spermatocytes.   70
Figure13.  Immunofliuorescence staining of GC-1 spg cells with antibodies to STK31 and γ-tubulin.                                                         71
Appendix 1. Known mouse genes expressed in spermatogonia but not in somatic tissues.                                                                     72
Appendix 2.  New spermatogonially expressed, germ-cell-specific genes in mouse, and their human orthologs                                             73
Appendix 3.  KARCA1 (Hs. 507290) expression profile by analysis of EST  counts .                                                                     74
Appendix 4.  Cell-cycle regulators which are significantly down-regulated in infertile men identified by microarray analysis.                             75
Appendix 5. The functional domains of KARCA1.                                76
Appendix 6.  The functional domains of STK31.                                77
Appendix 7. Phylogenetic analysis of human protein kinase family.            78
Appendix 8.  Stk31 expression in the oocyte and preimplantation embryos.     79
                                    

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