臺灣博碩士論文加值系統

摘要內容
在人工協助生殖技術的治療中，提昇胚胎的著床率一直是個難以解決的瓶頸問題。這是由於胚胎要能成功的著床必須同時具備有著床能力(implantation)的囊胚期胚胎以及具有胚胎接受能力的子宮。而在胚胎與子宮間剛開始進行的交互作用中，有許多因子參與進而影響著床。溶血磷脂酸(Lysophosphatidic acid, LPA)為一脂質分子，具有刺激卵子成熟，以及幫助哺乳類動物二或四細胞胚胎發育至囊胚期胚胎的能力。最近子宮中LPA3的接受器，被證實對於胚胎著床具有很大的影響。本研究的主旨為評估LPA對於胚胎著床能力的影響以及繼續探討其分子作用的機制。實驗結果我們發現在囊胚期的胚胎培養時若在培養液中加入LPA會使得胚胎於體外附著於matrigel的比率增加，尤其以100mM 濃度之LPA最顯著(62.4% ± 1.6% vs. 9.0% ± 9.0, p<0.05)。我們更進一步的建立假孕母鼠的胚胎植入模式，將胚胎培養在不同培養液中並植入老鼠子宮內，以觀察LPA對胚胎著床情形。在培養液中加入100mM LPA的一組，胚胎具有較未加入LPA之控制組高的著床比率(87.5% ± 7.2% vs. 66.7% ± 4.2%)，而在加入LPA的抑制劑(Ki16425)組相較於對側控制組的子宮著床率，其著床數目則有減少的情形(25.0% ± 14.4% vs. 70.8% ± 4.2%, p <0.05)。為了深入探討LPA影響胚胎著床的分子機制，我們利用寡核苷酸微陣列分析法(Oligonucleotide microarray)，分析經由100mM LPA添加培養的胚胎所影響的基因表現。經由結果分析後，有35個基因於加入100mM LPA後使得表現量增加(Normalized Expression Ratio, NER＞2)以及22個減少(NER< 0.5)的基因。在增加的基因中，我們發現Obox1基因有47倍的增加；Omt2b基因有37倍的增加；Oog1基因有28倍的增加；Btg4基因有25倍的增加；Trim61基因有22倍的增加；RGS2基因有21倍的增加。特別是RGS2基因，過去研究中有被提出在著床上扮演著重要角色。經由Real-time quantitative PCR的確認下，證明了加入100mM LPA於胚胎培養液中會使得胚胎上RGS2的mRNA表現量較控制組增加27.0 ± 5.5倍，而在Ki16425的作用下會抑制胚胎上RGS2的mRNA表現量，下降至控制組的4.5 ± 0.8倍。再以Matrigel 進行體外模擬著床分析，當胚胎給予100mM LPA後再以RGS2 inhibitor抑制其作用，發現黏著於Matrigel的比率會明顯下降(77.5% ± 4.2% vs. 21.7% ± 4.5%, p<0.01) ，經由此結果我們進一步確認LPA經由RGS2增加胚胎著床率。在分析LPA活化RGS2 pathway中的訊息傳遞作用中，我們觀察LPA對胚胎壓力纖維(stress fiber)的影響。經由FITC-labeled phalloidin的免疫螢光染色結果與控制組相比較，當胚胎給予100mM LPA時，螢光出現於胚胎移行之觸角部分比率最高 (38.9% vs. 20.8%)，而在其他抑制組部分，螢光多呈現散佈於細胞質中之型態。綜合上述實驗結果，我們確認LPA可經由RGS2調控，提高形成stress fiber組成的能力，並且增加胚胎著床的能力。

To improve the implantation rate is an important issue in the assisted reproductive techonology. The successful implantation depends upon the implantation-competent blastocyst and the receptive uterus. This process is initiated via blastocyst-endometrium interaction and delicately regulated by multiple factors. Lysophosphatidic acid (LPA) is a lipid-based signaling molecule and essential to mammalian oocyte maturation and preimplantation development. LPA3 had been demonstrated that it participates in implantation process through receptor-mediated signaling in uterus but the detail mechanisms are unclear. In this study, we try to explore the role of LPA in this process. As the result, LPA supplementation enhanced the attachment rate of blastocysts on the matrigel, especially following 100 mM LPA treatment (62.4% ± 1.6% vs. 9.0% ± 9.0, p<0.05). In vivo mouse mode showed the LPA treated group had significantly higher implantation rate than the control group (87.5% ± 7.2% vs. 66.7% ± 4.2%, p<0.05). Moreover, the implantation rate was inhibited by Ki16425 (LPA inhibitor) (25.0% ± 14.4% vs. 70.8% ± 4.2%, p<0.05). To gain insights into the molecular mechanisms, we identified the candidate genes involved in this process including 35 up-regulated genes (Normalized Expression Ratio, NER＞2) and 22 down-regulated genes (NER＜0.5) by oligonucleotide microarray. The top five up-regulated gene was Obox1 (47 folded increase), Omt2b (37), Oog1 (28), Btg4 (25), Trim61 (22), and RGS2 (21). Content of the regulator of G-protein signaling protein 2 (RGS2) mRNA was confirmed with 27.0 ± 5.5 folded increase by real-time quantitative PCR analysis. By use of pharmalogical LPA inhibitor, RGS2 mRNA was reduced to 4.5 ± 0.8-folded (p=0.06). The augmented RGS2 expression was suppressed by LPA inhibitor and significantly reduced the attachment rate compared with LPA alone group (77.5% ± 4.2% vs. 21.7% ± 4.5%, p<0.01). Through RGS2 signaling pathway, LPA enhance blastocyst implantation ability .In addition, stress fiber organized via RGS2 activation and required for embryo implantation process. All the treated embryos were stain with FITC-labeled phalloidin to observe the distribution of actin filament. We found the well-organized stress fiber distributed in the LPA-treated embryos, and localized at the embryo migration facade (38.9% vs. 20.8%). However, in the inhibitor groups the granules-like actin filament only generally distributed in blastocyst cytoplasm. These results indicate that through RGS2 signaling pathway, LPA may enhance blastocyst implantation ability by regulation of actin filament organization.

中文摘要 I
英文摘要 IV
目 錄 X
圖表目次 XI
縮 寫 表 XIV
第一章 緒論 1
第一節 研究背景 2
一、 不孕現況
二、 著床失敗的因素
三、 培養液於胚胎著床時扮演的角色
第二節 研究動機 5
第三節 研究目的 5

第二章 文獻探討 6
第一節 哺乳類胚胎著床的機制 7
一、 著床的發生
二、 著床時子宮的型態
三、 著床前胚胎發育與基因的活化
四、 著床時參與子宮內膜蛻膜化的賀爾蒙
五、 著床時參與胚胎與子宮間訊息傳遞的因子
六、 著床時細胞週期的調控
第二節 LPA的生化特性 15
一、 LPA的發現
二、 LPA的結構
三、 LPA的生化特性
四、 LPA存於細胞表面與細胞內的接受器
五、 LPA之G蛋白偶合型接受器(G protein couple receptor)
第三節LPA的生理功能 21
一、 LPA的分佈
二、 LPA在生理與病理的作用
第四節LPA對生殖系統的影響 23
一、 LPA在生殖道的重要性
二、 LPA對胚胎發育的影響
第五節LPA抑制劑的特性及作用 25
一、 Ki16425的生化特性
二、 Ki16425藥理學的特性

三、 Ki16425的抑制能力
第六節G蛋白訊號調節因子2 27
(regulators of G protein signaling-2, RGS2)
第三章 研究方法 30
第一節、實驗設計 31
一、 研究目的(一)
探討在體外培養時LPA對於胚胎著床能力的影響
二、 研究目的(二)
探討以LPA培養的胚胎移植老鼠體內著床的能力
三、 研究目的(三)
探討LPA影響著床時所參與的基因
四、 研究目的(四)
探討LPA增加著床能力之可能機制
第二節、實驗方法與材料 32
一、 分析體外培養時LPA對於胚胎著床能力影響
1. 胚胎培養環境的控制
2. 老鼠超排卵刺激及胚胎的收集
3. 紀錄胚胎孵化之速度以評估培養環境的影響
4. 以Matrigel評估體外胚胎著床的能力
5. LPA作用於鼠胚之劑量反應評估
二、 分析以LPA培養的胚胎移植於老鼠體內之著床能力影響
1. 結紥輸精管公鼠之製備
2. 假孕母鼠之子宮移植胚胎
3. 胚胎植入後觀察子宮內著床的情形
4. 添加LPA抑制劑觀察對胚胎著床的影響
三、 分析LPA如何影響著床及其中間可能參與的重要基因
1. 微陣列晶片分析
2. 即時定量聚合酶連鎖反應法
四、 分析LPA增加著床能力之可能機制
胚胎免疫染色法
第四章 實驗結果. 43
一、 結果(一)：在體外培養時LPA對於鼠胚著床能力影響的 44
以Matrigel 評估LPA對於老鼠胚胎發育的影響及劑量-?{反應評估
二、 結果(二)：以LPA培養的胚胎移置老鼠體內之著床能力之結果 45
三、 結果(三)：LPA影響著床時中間可能參與的重要基因 45
1. 微陣列晶片分析結果
2. 利用即時定量聚合酶連鎖反應確認結果
3. 利用Matrigel體外胚胎培養系統，探討LPA以及參與LPA作用過程的RGS2基因對胚胎孵化與著床能力影響之結果。
四、 結果(四)：LPA增加著床能力之可能機制 48
胚胎免疫染色法之結果
第五章 討論 49
第六章 圖表 58
第七章 參考文獻 90

Adamson, G. D., de Mouzon, J., Lancaster, P., Nygren, K. G., Sullivan, E., and Zegers-Hochschild, F. (2006). World collaborative report on in vitro fertilization, 2000. Fertil Steril 85, 1586-1622.
Albertini, D. F., Overstrom, E. W., and Ebert, K. M. (1987). Changes in the organization of the actin cytoskeleton during preimplantation development of the pig embryo. Biol Reprod 37, 441-451.
Anliker, B., and Chun, J. (2004). Lysophospholipid G protein-coupled receptors. J Biol Chem 279, 20555-20558.
Aoki, J. (2004). Mechanisms of lysophosphatidic acid production. Semin Cell Dev Biol 15, 477-489.
Aoki, J., Taira, A., Takanezawa, Y., Kishi, Y., Hama, K., Kishimoto, T., Mizuno, K., Saku, K., Taguchi, R., and Arai, H. (2002). Serum lysophosphatidic acid is produced through diverse phospholipase pathways. J Biol Chem 277, 48737-48744.
Aplin, J. D. (1997). Adhesion molecules in implantation. Rev Reprod 2, 84-93.
Armant, D. R., Wang, J., and Liu, Z. (2000). Intracellular signaling in the developing blastocyst as a consequence of the maternal-embryonic dialogue. Semin Reprod Med 18, 273-287.
Artley, J. K., Braude, P. R., and Johnson, M. H. (1992). Gene activity and cleavage arrest in human pre-embryos. Hum Reprod 7, 1014-1021.
Brindley, D. N., English, D., Pilquil, C., Buri, K., and Ling, Z. C. (2002). Lipid phosphate phosphatases regulate signal transduction through glycerolipids and sphingolipids. Biochim Biophys Acta 1582, 33-44.
Budnik, L. T., and Mukhopadhyay, A. K. (2001). Lysophosphatidic acid antagonizes the morphoregulatory effects of the luteinizing hormone on luteal cells: possible role of small Rho-G-proteins. Biol Reprod 65, 180-187.
Budnik, L. T., and Mukhopadhyay, A. K. (2002). Lysophosphatidic acid and its role in reproduction. Biol Reprod 66, 859-865.
Carnegie, J., Claman, P., Lawrence, C., and Cabaca, O. (1995). Can Matrigel substitute for Vero cells in promoting the in-vitro development of mouse embryos? Hum Reprod 10, 636-641.
Carson, D. D., Bagchi, I., Dey, S. K., Enders, A. C., Fazleabas, A. T., Lessey, B. A., and Yoshinaga, K. (2000). Embryo implantation. Dev Biol 223, 217-237.
Chakraborty, I., Das, S. K., Wang, J., and Dey, S. K. (1996). Developmental expression of the cyclo-oxygenase-1 and cyclo-oxygenase-2 genes in the peri-implantation mouse uterus and their differential regulation by the blastocyst and ovarian steroids. J Mol Endocrinol 16, 107-122.
Chrzanowska-Wodnicka, M., and Burridge, K. (1994). Tyrosine phosphorylation is involved in reorganization of the actin cytoskeleton in response to serum or LPA stimulation. J Cell Sci 107 (Pt 12), 3643-3654.
Ding, Y. Q., Zhu, L. J., Bagchi, M. K., and Bagchi, I. C. (1994). Progesterone stimulates calcitonin gene expression in the uterus during implantation. Endocrinology 135, 2265-2274.
Enders, A. C., and Schlafke, S. (1969). Cytological aspects of trophoblast-uterine interaction in early implantation. Am J Anat 125, 1-29.
Fang, X., Gaudette, D., Furui, T., Mao, M., Estrella, V., Eder, A., Pustilnik, T., Sasagawa, T., Lapushin, R., Yu, S., et al. (2000). Lysophospholipid growth factors in the initiation, progression, metastases, and management of ovarian cancer. Ann N Y Acad Sci 905, 188-208.
Fazleabas, A. T., and Kim, J. J. (2003). Development. What makes an embryo stick? Science 299, 355-356.
Genbacev, O. D., Prakobphol, A., Foulk, R. A., Krtolica, A. R., Ilic, D., Singer, M. S., Yang, Z. Q., Kiessling, L. L., Rosen, S. D., and Fisher, S. J. (2003). Trophoblast L-selectin-mediated adhesion at the maternal-fetal interface. Science 299, 405-408.
Gianaroli, L., Seracchioli, R., Ferraretti, A. P., Trounson, A., Flamigni, C., and Bovicelli, L. (1986). The successful use of human amniotic fluid for mouse embryo culture and human in vitro fertilization, embryo culture, and transfer. Fertil Steril 46, 907-913.
Giancotti, F. G., and Ruoslahti, E. (1999). Integrin signaling. Science 285, 1028-1032.
Goetzl, E. J., and An, S. (1998). Diversity of cellular receptors and functions for the lysophospholipid growth factors lysophosphatidic acid and sphingosine 1-phosphate. Faseb J 12, 1589-1598.
Graves, C. N., and Biggers, J. D. (1970). Carbon dioxide fixation by mouse embryos prior to implantation. Science 167, 1506-1508.
Hambartsoumian, E. (1998). Endometrial leukemia inhibitory factor (LIF) as a possible cause of unexplained infertility and multiple failures of implantation. Am J Reprod Immunol 39, 137-143.
Hepler, J. R. (1999). Emerging roles for RGS proteins in cell signalling. Trends Pharmacol Sci 20, 376-382.
Heximer, S. P., Lim, H., Bernard, J. L., and Blumer, K. J. (2001). Mechanisms governing subcellular localization and function of human RGS2. J Biol Chem 276, 14195-14203.
Hinokio, K., Yamano, S., Nakagawa, K., Iraharaa, M., Kamada, M., Tokumura, A., and Aono, T. (2002). Lysophosphatidic acid stimulates nuclear and cytoplasmic maturation of golden hamster immature oocytes in vitro via cumulus cells. Life Sci 70, 759-767.
Huang, Z. P., Ni, H., Yang, Z. M., Wang, J., Tso, J. K., and Shen, Q. X. (2003). Expression of regulator of G-protein signalling protein 2 (RGS2) in the mouse uterus at implantation sites. Reproduction 126, 309-316.
Huet-Hudson, Y. M., and Dey, S. K. (1990). Requirement for progesterone priming and its long-term effects on implantation in the mouse. Proc Soc Exp Biol Med 193, 259-263.
Kehrl, J. H., and Sinnarajah, S. (2002). RGS2: a multifunctional regulator of G-protein signaling. Int J Biochem Cell Biol 34, 432-438.
Kobayashi, T., Yamano, S., Murayama, S., Ishikawa, H., Tokumura, A., and Aono, T. (1994). Effect of lysophosphatidic acid on the preimplantation development of mouse embryos. FEBS Lett 351, 38-40.
Kunikata, K., Yamano, S., Tokumura, A., and Aono, T. (1999). Effect of lysophosphatidic acid on the ovum transport in mouse oviducts. Life Sci 65, 833-840.
Larue, L., Ohsugi, M., Hirchenhain, J., and Kemler, R. (1994). E-cadherin null mutant embryos fail to form a trophectoderm epithelium. Proc Natl Acad Sci U S A 91, 8263-8267.
Lessey, B. A. (2000). The role of the endometrium during embryo implantation. Hum Reprod 15 Suppl 6, 39-50.
Ma WG, S. H., Das SK, Paria BC, Dey SK (2003). Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation. Proc Natl Acad Sci USA 100, 2963-2968.
Marcus, G. J., and Shelesnyak, M. C. (1968). Studies on the mechanism of nidation. 33. Coital elevation of uterine histamine content. Acta Endocrinol (Copenh) 57, 136-141.
Martin, K. L., Barlow, D. H., and Sargent, I. L. (1998). Heparin-binding epidermal growth factor significantly improves human blastocyst development and hatching in serum-free medium. Hum Reprod 13, 1645-1652.
Moolenaar, W. H. (1995). Lysophosphatidic acid signalling. Curr Opin Cell Biol 7, 203-210.
Neitzel, K. L., and Hepler, J. R. (2006). Cellular mechanisms that determine selective RGS protein regulation of G protein-coupled receptor signaling. Semin Cell Dev Biol 17, 383-389.
Noguchi, K., Ishii, S., and Shimizu, T. (2003). Identification of p2y9/GPR23 as a novel G protein-coupled receptor for lysophosphatidic acid, structurally distant from the Edg family. J Biol Chem 278, 25600-25606.
Noyes, R. W., Hertig, A. T., and Rock, J. (1975). Dating the endometrial biopsy. Am J Obstet Gynecol 122, 262-263.
Ohta, H., Sato, K., Murata, N., Damirin, A., Malchinkhuu, E., Kon, J., Kimura, T., Tobo, M., Yamazaki, Y., Watanabe, T., et al. (2003). Ki16425, a subtype-selective antagonist for EDG-family lysophosphatidic acid receptors. Mol Pharmacol 64, 994-1005.
Ola, B., and Li, T. C. (2006). Implantation failure following in-vitro fertilization. Curr Opin Obstet Gynecol 18, 440-445.
Paria, B. C., Das, S. K., Andrews, G. K., and Dey, S. K. (1993). Expression of the epidermal growth factor receptor gene is regulated in mouse blastocysts during delayed implantation. Proc Natl Acad Sci U S A 90, 55-59.
Paria, B. C., Huet-Hudson, Y. M., and Dey, S. K. (1993). Blastocyst''s state of activity determines the "window" of implantation in the receptive mouse uterus. Proc Natl Acad Sci U S A 90, 10159-10162.
Paria, B. C., Reese, J., Das, S. K., and Dey, S. K. (2002). Deciphering the cross-talk of implantation: advances and challenges. Science 296, 2185-2188.
Paria, B. C., Zhao, X., Das, S. K., Dey, S. K., and Yoshinaga, K. (1999). Zonula occludens-1 and E-cadherin are coordinately expressed in the mouse uterus with the initiation of implantation and decidualization. Dev Biol 208, 488-501.
Petraglia, F., Santuz, M., Florio, P., Simoncini, T., Luisi, S., Plaino, L., Genazzani, A. R., Genazzani, A. D., and Volpe, A. (1998). Paracrine regulation of human placenta: control of hormonogenesis. J Reprod Immunol 39, 221-233.
Pool, T. B. (2004). Development of culture media for human assisted reproductive technology. Fertil Steril 81, 287-289.
Psychoyos, A. (1973). Hormonal control of ovoimplantation. Vitam Horm 31, 201-256.
Raab, G., Kover, K., Paria, B. C., Dey, S. K., Ezzell, R. M., and Klagsbrun, M. (1996). Mouse preimplantation blastocysts adhere to cells expressing the transmembrane form of heparin-binding EGF-like growth factor. Development 122, 637-645.
Reddy, K. V., and Meherji, P. K. (1999). Integrin cell adhesion molecules in endometrium of fertile and infertile women throughout menstrual cycle. Indian J Exp Biol 37, 323-331.
Roberts, R. M., Ealy, A. D., Alexenko, A. P., Han, C. S., and Ezashi, T. (1999). Trophoblast interferons. Placenta 20, 259-264.
Schlafke, S., and Enders, A. C. (1975). Cellular basis of interaction between trophoblast and uterus at implantation. Biol Reprod 12, 41-65.
Sengupta, S., Wang, Z., Tipps, R., and Xu, Y. (2004). Biology of LPA in health and disease. Semin Cell Dev Biol 15, 503-512.
Shiokawa, S., Sakai, K., Akimoto, Y., Suzuki, N., Hanashi, H., Nagamatsu, S., Iwashita, M., Nakamura, Y., Hirano, H., and Yoshimura, Y. (2000). Function of the small guanosine triphosphate-binding protein RhoA in the process of implantation. J Clin Endocrinol Metab 85, 4742-4749.
Sinnarajah, S., Dessauer, C. W., Srikumar, D., Chen, J., Yuen, J., Yilma, S., Dennis, J. C., Morrison, E. E., Vodyanoy, V., and Kehrl, J. H. (2001). RGS2 regulates signal transduction in olfactory neurons by attenuating activation of adenylyl cyclase III. Nature 409, 1051-1055.
Smith, W. L., and Dewitt, D. L. (1996). Prostaglandin endoperoxide H synthases-1 and -2. Adv Immunol 62, 167-215.
Song, H., Lim, H., Das, S. K., Paria, B. C., and Dey, S. K. (2000). Dysregulation of EGF family of growth factors and COX-2 in the uterus during the preattachment and attachment reactions of the blastocyst with the luminal epithelium correlates with implantation failure in LIF-deficient mice. Mol Endocrinol 14, 1147-1161.
Stewart, C. L., and Cullinan, E. B. (1997). Preimplantation development of the mammalian embryo and its regulation by growth factors. Dev Genet 21, 91-101.
Stromstedt, M., Keeney, D. S., Waterman, M. R., Paria, B. C., Conley, A. J., and Dey, S. K. (1996). Preimplantation mouse blastocysts fail to express CYP genes required for estrogen biosynthesis. Mol Reprod Dev 43, 428-436.
Summers, M. C., and Biggers, J. D. (2003). Chemically defined media and the culture of mammalian preimplantation embryos: historical perspective and current issues. Hum Reprod Update 9, 557-582.
Tervit, H. R., Whittingham, D. G., and Rowson, L. E. (1972). Successful culture in vitro of sheep and cattle ova. J Reprod Fertil 30, 493-497.
Tigyi, G., Hong, L., Yakubu, M., Parfenova, H., Shibata, M., and Leffler, C. W. (1995). Lysophosphatidic acid alters cerebrovascular reactivity in piglets. Am J Physiol 268, H2048-2055.
Tokumura, A. (2002). Physiological and pathophysiological roles of lysophosphatidic acids produced by secretory lysophospholipase D in body fluids. Biochim Biophys Acta 1582, 18-25.
Tokumura, A., Harada, K., Fukuzawa, K., and Tsukatani, H. (1986). Involvement of lysophospholipase D in the production of lysophosphatidic acid in rat plasma. Biochim Biophys Acta 875, 31-38.
Tokumura, A., Iimori, M., Nishioka, Y., Kitahara, M., Sakashita, M., and Tanaka, S. (1994). Lysophosphatidic acids induce proliferation of cultured vascular smooth muscle cells from rat aorta. Am J Physiol 267, C204-210.
Tokumura, A., Kanaya, Y., Miyake, M., Yamano, S., Irahara, M., and Fukuzawa, K. (2002). Increased production of bioactive lysophosphatidic acid by serum lysophospholipase D in human pregnancy. Biol Reprod 67, 1386-1392.
Tokumura, A., Miyake, M., Nishioka, Y., Yamano, S., Aono, T., and Fukuzawa, K. (1999). Production of lysophosphatidic acids by lysophospholipase D in human follicular fluids of In vitro fertilization patients. Biol Reprod 61, 195-199.
Tokumura, A., Yamano, S., Aono, T., and Fukuzawa, K. (2000). Lysophosphatidic acids produced by lysophospholipase D in mammalian serum and body fluid. Ann N Y Acad Sci 905, 347-350.
Ujioka, T., Russell, D. L., Okamura, H., Richards, J. S., and Espey, L. L. (2000). Expression of regulator of G-protein signaling protein-2 gene in the rat ovary at the time of ovulation. Biol Reprod 63, 1513-1517.
Vacca, A., Ribatti, D., Roncali, L., and Dammacco, F. (1995). Angiogenesis in B cell lymphoproliferative diseases. Biological and clinical studies. Leuk Lymphoma 20, 27-38.
Wang, W. H., Abeydeera, L. R., Han, Y. M., Prather, R. S., and Day, B. N. (1999). Morphologic evaluation and actin filament distribution in porcine embryos produced in vitro and in vivo. Biol Reprod 60, 1020-1028.
Westermann, A. M., Havik, E., Postma, F. R., Beijnen, J. H., Dalesio, O., Moolenaar, W. H., and Rodenhuis, S. (1998). Malignant effusions contain lysophosphatidic acid (LPA)-like activity. Ann Oncol 9, 437-442.
Xu, Y., Gaudette, D. C., Boynton, J. D., Frankel, A., Fang, X. J., Sharma, A., Hurteau, J., Casey, G., Goodbody, A., Mellors, A., and et al. (1995). Characterization of an ovarian cancer activating factor in ascites from ovarian cancer patients. Clin Cancer Res 1, 1223-1232.
Xu, Y., Shen, Z., Wiper, D. W., Wu, M., Morton, R. E., Elson, P., Kennedy, A. W., Belinson, J., Markman, M., and Casey, G. (1998). Lysophosphatidic acid as a potential biomarker for ovarian and other gynecologic cancers. Jama 280, 719-723.
Ye, X., Hama, K., Contos, J. J., Anliker, B., Inoue, A., Skinner, M. K., Suzuki, H., Amano, T., Kennedy, G., Arai, H., et al. (2005). LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing. Nature 435, 104-108.
Yoshida, K., Taga, T., Saito, M., Suematsu, S., Kumanogoh, A., Tanaka, T., Fujiwara, H., Hirata, M., Yamagami, T., Nakahata, T., et al. (1996). Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. Proc Natl Acad Sci U S A 93, 407-411.
Yoshinaga, K. (1988). Uterine receptivity for blastocyst implantation. Ann N Y Acad Sci 541, 424-431.
Yoshinaga, K., and Adams, C. E. (1966). Delayed implantation in the spayed, progesterone treated adult mouse. J Reprod Fertil 12, 593-595.
Zhang, Q., Checovich, W. J., Peters, D. M., Albrecht, R. M., and Mosher, D. F. (1994). Modulation of cell surface fibronectin assembly sites by lysophosphatidic acid. J Cell Biol 127, 1447-1459.
Zhao, X., Ma, W., Das, S. K., Dey, S. K., and Paria, B. C. (2000). Blastocyst H(2) receptor is the target for uterine histamine in implantation in the mouse. Development 127, 2643-2651.