/ Mini Review www.cjb.org.cn 2010 2 26 2 : 106-114 ACTA BIOPHYSICA SINICA 2010 Vol.26 No.2: 106-114 1, 1, 2 1, 1. 150040 2. 361005 2009-11-22 2010-01-03 (0451)82191784 E-mail chhshan@sina.com,,,,,, ; ; ; Q492 R321.3 0 1~4 4~5.5 5.5 1 1 1 1 4 4.5 4 5.5 1 4 5.5 Fig.1 The process of embryo implantation Adult females were mated with fertile males of the same strain to induce pregnancy (day 1=day of vaginal plug), embryo implants on the midnight of day 4, when it is day 4.5 of pregnancy. Implantation: from day 4 to day 5.5 of pregnancy; pre-implantation: from day 1 to day 4 of pregnancy; post-implantation: after day 5.5 of pregnancy 106
Mini Review / 1 1.1 DNA A10 homeboxa10 HOXA10 A11 homebox A11 HOXA11 H6 3 H6 homeobox 3 Hmx3 1~2 HOXA10 3 5~8 [1] 8 HOXA10 HOXA10 [2] FKHR HOXA10-1 insulin-like growth factor binding protein-1 IGFBP-1 IGFBP-1 [3~4] HOXA10 [5] β3 HOXA10 β3 mrna HOXA10 β3 IGFBP-1 HOXA11 Gendron [6] 4 HOXA11 5~8 HOXA11 HOXA11 [7] leuckemia inbibitory factor LIF HOXA11 LIF HOXA10 HOXA11 mrna HOXA10 HOXA11 [8] HOXA11 Hmx3 Hmx3 Hmx3 -/- Hmx3 -/- 88% Hmx3 -/- Wnt wingless-related MMTV integration site Wnta5 Wnt7a Wnt4 LIF LIF [9] Hmx3 LIF www.cjb.org.cn ACTA BIOPHYSICA SINICA 107
/ Mini Review 2010 26 2 1.2 progesterone receptor PR α estrogen receptor α ERα β estrogen receptor β ERβ PR PR-A PR-B PR 1~2 3~4 5 PR 6~8 PR-A PR-B PR-A PR-B PR -/- [10] PR SRC FK506 FK506-binding protein Fkbp52 Fkbp52 PR Fkbp52 PR Fkbp52 PR Ihh [7] Indian hedgehog ERa ERβ [11] ERE -1 activatorprotein-1 AP-1 1 specificity protein 1 Sp1 kβ Nuclear factor-kappa β NF-κβ [12] 1~2 ERa mrna 3~4 5 [13] 6~8 ERa -/- ERa -/- PR HOXA10 2 cyclooxygenase2 COX 2 LIF PR HOXA10 COX2 LIF ERa -/- PR HOXA10 mrna PR LIF COX2 mrna ERa -/- [14] ERa ERβ mrna [11] ERβ ERa 2 2.1 STAT STAT 6 STAT 3 signal transducer and activator of transcription 3 STAT3 108 ACTA BIOPHYSICA SINICA Vol.26 No.2 Feb. 2010
Mini Review / 4 STAT3 5 [15] STAT3 [16] STAT3 JAK/STAT [17] STAT3 STAT3 2.2 ( basic transcription element-binding protein BTEB) Krüppel GC GT/CACC box Snail -1 (basic transcription element-binding protein-1 BTEB-1) BTEB1 -/- 1~6 (BrdU ) (TUNEL) PR ( ) Michael [18] BTEB1 -/- BrdU PR 4 ( 3 ) 3 BrdU PR 3 5 BTEB1 -/- 4 PR BTEB1 -/- Michael BTEB1 -/- BTEB1 Snail 1~4 5 [19] Snail Snail Vega [20] Snail Cyclin D2 Cyclin D2 Snail E-box Herfs [21] Snail Snail Slug Snail [22] RT-PCR Slug 1~3 4 5 6~7 Slug E- E-box E- www.cjb.org.cn ACTA BIOPHYSICA SINICA 109
/ Mini Review 2010 26 2 [23] E- Slug 2.3 E26 ETS PEA3 COX2 PEA3 ERM ER81 PEA3 4~5 ERM 4 5 ER81 PEA3 1 4 5 8 ERM PEA3 ER81 Koo [24] ERM ER81 PEA3 PEA3 [25] [26] 2.4 δ (peroxisome proliferator activated receptorδ PPARδ) PPARδ 1~4 5 5 PPARδ [27] 6 PPARδ -/- PPARδ -/- PPARδ PPARδ [28] COX2 5 [29] PPARδ COX2 COX2 PPARδ COX2 PPARδ PPARδ AKT LIF-STAT3 [27] 3 lysophosphatidic acid receptor3 LPA3 RT-PCR Western blot LPA3 1~6 3 4 5 6 [30] LPA3 LPA3 COX2 E2 I2 E2 I2 LPA3 [31] LPA3 COX2 [32] 1 110 ACTA BIOPHYSICA SINICA Vol.26 No.2 Feb. 2010
Mini Review / 1 Table 1 A partial list of transcription factors found to be critical for uterine function and implantation Gene Expression characteristics Phenotype Ref HOXA10 D1~2 highly expressed in LE and GE D3 expressed decreased in LE and GE Important for implantation and decidualization [1,2,5] D5~8 expressed in DC HOXA11 D4 highly expressed Importan for implantation and [6,7] D5~8 expressed in S decidualization Hmx3 Primarily expressed in the myometrium Essential for implantation [9] ERa D1~2 expressed in LE and GE Uterine hypoplasia and impaired [13,14] D3~4 expressed in S implantation D5 highly expressed in LE and GE, but decreased in S D6~8 expressed in S PR D1~2 expressed decreased in epithelium Failure of decidualization [10] D5 only expressed in S D6~8 expressed in DC STAT3 D4.5 only highly phosphorylate in LE Important for implantation and [15, 16] D5 strongly phosphorylate in LE and S decidualization Sainl D1~4 lowly expressed Help embryo to invade the [19,21] D5 transiently expressed in S endometrium Slug D1~3 increasely expressed in epithelium Important for receptivity and [22,23] and S invading the endometrium ETS family D4 ERM is highly expressed in epithelium and S D4~5 ER81, PEA3 are lowly expressed in S D8 ERM, PEA3 are highly expressed in embryo ERM is implicated in the early event of implantation ER81 is involved in the establishment of vasculature for placental development. PEA3 is important for early embryogenesis [25] PPARδ D1~4 lowly expressed Important for implantation and [27,28] D5 only expreessed in S around the decidualization blastocyst implantation LPA3 D1~3 lowly expressed Important for delayed [30~32] D4 highly expressed implantation and embryo D5~6 Sharp declined spacing LE GE S DC D 1 (D1) LE: lumina epithelium; GE: glandular epithelium; S: stroma; DC: decidual cell; D: day of pregnancy; D1=day of vaginal plug www.cjb.org.cn ACTA BIOPHYSICA SINICA 111
/ Mini Review 2010 26 2 3 2 (caudal relatedhomeodomain transcription2 CDX2) TEA 4 ( TEA domain family member4 TEAD4) 1 (heat shock transcription factor 1 HSF1) HOXA10 [33,34] (Yin Yang-1 YY1) Kruppel 6 ( Krüippel-like [35,36] factor 6 KLF6) 4 RNA 1. Satokata I, Benson G, Maas R. Sexually dimorphic sterility, 2008, 39(3): 275~278 phenotypes in Hoxa10 deficient mice. Nature, 1995, Chi YJ, Yang ZM. Roles of progesterone-regulated genes 374(6521): 460~463 in embryo implantation. Progress in Physiological Sciences, 2.,.. 2008, 39(3): 275~278, 2008, 43(4): 133~139 8. Taylor HS, Igarashi P, Olive DL, Arici A. Sex steroids Tian Z, Yang ZM. The establishment and molecular mediate HOXA11 expression in the human peri-implantation regulation of uterine receptivity. Chinese Journal of endometrium. J Clin Endocrinol Metab, 1999, 84 (3): Zoology, 2008, 43(4): 133~139 1129~1135 3. Fazleabas AT, Kim JJ, Strakova Z. Implantation: embryonic 9. Kimber SJ. Leukaemia inhibitory factor in implantation and signals and the modulation of the uteri environment. uterine biology. Reproduction, 2005, 130(2):131~145 Placenta, 2004, 25: 26~31 10. Wang H, Dey SK. Roadmap to embryo implantation: clues 4. Kim JJ, Fazleabas AT. Uterine receptivity and implantation: from mouse models. Nat Rev Genet, 2006, 7(3): 185~199 the regulation and action of insulin-like growth factor 11. Dey SK, Lim H, Das SK, Reese J, Paria BC, Daikoku T, binding protein-1 (IGFBP-1), HOXA10 and forkhead Wang H. Molecular cues to implantation. Endocrine, 2004, transcription factor-1 (FOXO-1) in the baboon endometrium. 25(3): 341~373 Reprod Biol Endocrinol, 2004, 2: 34 12. Matthews J, Wihlén B, Tujague M, Wan J, Str 觟 m A, 5. Du H, Taylor HS. Molecular regulation of müllerian Gustafsson JA. Estrogen receptor (ER) beta modulates development by hoxgenes. Ann NY Acad Sci, 2004, 1034: ERalpha-mediated transcriptional activation by altering the 152~165 recruitment of c-fos and c-jun to estrogen-responsive 6. Wong KH, Wintch HD, Capecchi MR. Hoxa11 regulates promoters. Mol Endocrinol, 2006, 20(3): 534~543 stromal cell death and proliferation during neonatal uterine development. Mol Endocrinol, 2004, 18(1): 184~193 13.,.., 2009, 40(4): 345~349 7.,.. Yang XL, Yang ZM. Regulation and function of nuclear 112 ACTA BIOPHYSICA SINICA Vol.26 No.2 Feb. 2010
Mini Review / receptors during embryo implantation. Progress in cancer cells. Acta Biochim Biophys Sin, 2009, 41(1): 63~68 Physiological Sciences, 2009, 40(4): 345~349 26. Cowden Dahl KD, Zeineldin R, Hudson LG. PEA3 is 14. Curtis H, Goulding EH, Ddy EM, Korach KS. Studies using necessary for optimal epidermal growth factor receptorstimulated the estrogen receptor-knockout uterus demonstrate that matrix metalloproteinase expression and invasion implantation but not decidualization-associated signaling is of ovarian tumor cells. Mol Cancer Res, 2007, 5 (5): estrogen dependent. Biol Reprod, 2002, 67: 1268~1277 15. Teng CB, Diao HL, Ma XH, Xu LB, Yang ZM. Differential 413~421 27. Ding NZ, Teng CB, Ma H, Ni H, Ma XH, Xu LB, Yang expressionand activation of Stat3 during mouse embryo ZM. Peroxisome proliferator activated receptor delta implantation and decidualization. Mol Reprod Dev, 2004, expression and regulation in mouse uterus during mmbryo 69(1): 1~10 implantation and decidualization. Molecula Reproduction and 16.,. STAT3 Development, 2003, (66): 218~224., 2007, 22(13): 1800~1802 28. Wang H, Xie H, Sun X, Tranguch S, Zhang H, Jia X, Zhao YQ, Zhang HW. Expression and activation of STAT3 Wang D, Das SK, Desvergne B, Wahli W, DuBois RN, in endometrium during peri-implantation period of mouse Dey SK. Stage-specific integration of maternal and embryo. Maternal and Child Health Care of China, embryonic peroxisome proliferator-activated receptor (PPAR) 2007, 22(13): 1800~1802 signaling is critical to pregnancy success. J Biol Chem, 17. Fitzgerald JS, Poehlmann TG, Schleussner E, Markert UR. 2007, 282(52): 37770~37782 Trophoblast invasion: the role of intracellular cytokine 29. Lee KY, Jeong JW, Tsai SY, Lydon JP, DeMayo FJ. signalling via signal transducer and activator of Mouse models of implantation. Trends Endocrinol Metab, transcription 3 (STAT3). Hum Reproduction Update, 2008, 14(4): 335~344 18. Velarde MC, Geng Y, Eason RR, Simmen FA, Simmen 2007, 18(6): 234~239 30. Hama K, Aoki J, Inoue A, Endo T, Amano T, Motoki R, Kanai M, Ye X, Chun J, Matsuki N, Suzuki H, Shibasaki RC. Null mutation of Krüppel Like Factor9/Basic M, Arai H. Embryo spacing and implantation timing are transcription element binding protein-1 alters differentially regulated by LPA3-mediated Lysophosphatidic peri-implantation uterine development in mice. Biol Reprod, 2005, 73(3): 472~481 acid signaling in mice. Biol Reprod, 2007, 77(6): 954~959 31. Ye X, Hama K, Contos JJ, Anliker B, Inoue A, Skinner 19. Ma XH, Hu SJ, Yu H, Xu LB, Yang ZM. Differential MK, Suzuki H, Amano T, Kennedy G, Arai H, Aoki J, expression of transcriptional repressor snail gene at Chun J. LPA3-mediated lysophosphatidic acid signalling in implantation site in mouse uterus. Mol Reprod, 2006, embryo implantation and spacing. Nature, 2005, 435(7038): 73(2): 133~141 20. Vega S, Morales AV, Oca 觡 a OH, Valdés F, Fabregat I, 104~108 32.,,,,,,. Nieto MA. Snail blocks the cell cycle and confers LPA3. resistance to cell death. Genes Dev, 2004, 18 (10):, 2009, 29(2): 178~182 1131~1143 Guo YH, Zhang L, Shao SX, Yin Q, Gong M, Zhang JP, 21. Herfs M, Hubert P, Kholod N, Caberg JH, Gilles C, Berx Zhao J. Effect of estrogen and progesterone on the G, Savagner P, Boniver J, Delvenne P. Transforming expression of LPA3 in uterine endometrium during growth factor-β1-mediated Slug and Snail transcription periimplantation. Basic & Clinical Medicine, 2009, 29 (2): factor up-regulation reduces the sensity of langerhans cells in epithelial metaplasia by affecting E-cadherin expression. 178~182 33. Nishioka N, Yamamoto S, Kiyonari H, Sato H, Sawada A, Am J Pathol, 2008, 172(5): 1391~1402 Ota M, Nakao K, Sasaki H. Tead4 is required for 22.,,,,. Sl ug specification of trophectoderm in pre-implantation mouse., 2008, 28(10): 77~581 Du F, Yang R, Wei SL, Ma HL, Wang QY. Expression of embryos. Mech Dev, 2008, 125(3-4): 270~283 34. Metchat A, Akerfelt M, Bierkamp C, Delsinne V, Sistonen Slug gene in endometrium of early pregnant mouse. L, Alexandre H, Christians ES. Mammalian heat shock Reproduction & Contraception, 2008, 28(10): 577~581 factor 1 is essential for oocyte meiosis and directly 23. Boló s V, Peinado H, Pérez-Moreno MA, Fraga MF, regulates Hsp90alpha expression. J Biol Chem, 2009, Esteller M, Cano A. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal 284(14): 9521~9528 35. Affarel B, Gay F, Shi Y, Liu H, Huarte M, Wu S, Collins transitions: a comparison with Snail and E47 repressors. J T, Li E, Shi Y. Essential dosage-dependent functions of Cell Sci, 2003, 116(3): 499~511 the transcription factor Yin Yang 1 in late embryonic 24. Koo BT, Song H, Moon I, Han K, Chen C, Murphy K, Lim development and cell cycle progression, Mol Cell Biol, H. Differential expression of the PEA3 subfamily of ETS 2006, 26(9): 3565~3581 transcription factors in the mouse ovary andperiimplantation 36. Pearson R, Fleetwood J, Eaton S, Crossley M, Bao S. uterus. Reproduction, 2005, 129(5): 651~657 Krüppel-like transcription factors: a functional family. Int J 25. Hua D, Chen B, Bai M, Yu H, Wu X, Jin W. PEA3 Biochem Cell Biol, 2008, 40(10): 1996~2001 activates VEGF transcription in T47D and SKBR3 breast www.cjb.org.cn ACTA BIOPHYSICA SINICA 113
/ Mini Review 2010 26 2 Transcription Factors in Mammalian Peri-Implantation ZHANG Liying 1, WANG Lianbang 1, FENG Xuhui 2, SHAN Chunhua 1 1. Laboratory of Development Biology, Northeast Forestry University, Haerbin 150040, China 2. College of Life Science, Xiamen University, Xiamen 361005, China This work was supported by The project of introducing talents from northeast forestry university Received: Nov 22, 2009 Accepted: Jan 3, 2010 Corresponding author: SHAN Chunhua, Tel: +86(451)82191784, E-mail: chhshan@sina.com Abstract Embryo implantation is a complex physiological process, in which the reciprocal interaction between an implantation competent blastocyst and receptive uterus must be achieved. During periimplantation, maternal or embryonic transcription factors are spatio-temporal expressed. One transcription factor can control multiple target genes, and one gene can be controled by many transcription factors also, which forms a complex network of regulation. The role of transcription factors in peri-implantation were reviewed in this paper. Key Words Embryo implantation; Transcription factor; Decidualization; Receptivity 114 ACTA BIOPHYSICA SINICA Vol.26 No.2 Feb. 2010