利用基因敲除研究小鼠Dapper2基因的功能
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摘要
Dapper(Dpr)家族成员在胚胎发育过程中发挥着重要的功能,并且参与了多种信号通路的调节,主要包括TGF-β/Nodal,经典和非经典的Wnt信号通路。
目前,在小鼠中已发现三种Dpr家族成员,Dpr1-Dpr3。通过对他们时空表达谱的研究发现,三种Dpr均在胚胎的各时期表达,在成年组织的表达略有差异,但是在脑中的表达量都比较高。已有研究发现斑马鱼Dpr2通过促进Nodal/TGF-β的I型受体经溶酶体途径降解来调节其信号通路,体内功能实验证明斑马鱼Dpr2抑制Nodal信号的中胚层诱导活性。虽然小鼠Dpr2在体外能够抑制TGF-β信号,并且在斑马鱼胚胎中过表达也能减少一些中胚层特异基因的表达,但是关于小鼠Dpr2体内功能的研究还没有报道。
在本研究中,通过基因打靶技术制备了Dpr2基因完全敲除小鼠(Dpr2-/-)。但是却发现Dpr2-/-小鼠胚胎发育正常,并没有出现胚胎致死的表型。Dpr2-/-小鼠的囊胚同野生型的一样,可以从透明带中孵出并且拥有正常的Outgrowth。出生后的Dpr2-/-小鼠能够正常生长,雌雄均可育。对Dpr2-/-小鼠脑进行组织学分析没有发现任何异常,其神经干细胞的增殖同野生型小鼠也没有差别。本研究还发现Dpr2在成年小鼠的表皮及毛囊角质细胞中高表达,并且缺失Dpr2导致小鼠皮肤创伤愈合的再表皮化加快。进一步的研究证实,缺失Dpr2增强了角质细胞对TGF-β信号的反应性,并且TGF-β信号通过上调特定的integrin基因的表达来促进角质细胞的迁移。
由此可以得出如下结论:缺失Dpr2基因对于小鼠胚胎发育、生长和脑的形态没有影响,Dpr2通过抑制TGF-β信号来抑制创伤皮肤的再表皮化。
Transforming growth factor (TGF-β) signals regulate a variety of cellular events and play important roles in embryonic development. Members of the Dapper (Dpr)/Dact family play roles in regulating distinct signaling pathways, including TGF-β/Nodal as well as canonical and noncanonical Wnt pathways. Three mouse Dpr genes, Dpr1-Dpr3, are expressed in mouse embryos and in distinct adult tissues, particularly in the brain. It has been demonstrated that zebrafish Dpr2 modulates Nodal/TGF-βsignals by promoting lysosomal degradation of their receptors and inhibits mesoderm induction in zebrafish embryos. Mouse Dpr2 is able to antagonize TGF-β? signaling in vitro and ectopic expression in zebrafish embryos also results in reduction of mesoderm gene expression. However, functions of mDpr2 in vivo have not been reported.
In this study, Dpr2-deficient mice were generated by gene knockout approach. Dpr2 knockout (Dpr2-/-) embryos developed normally and they were alive at birth. Like wild-type blastocysts, the isolated Dpr2-/- E3.5 blastocysts hatched from the zona pellucida, and had normal Outgrowth. Postnatal Dpr2-/- mice were able to grow up and the adults were fertile. The distribution of Dpr2 transcripts in subregions of adult brain of mice was examined in details. Dpr2 appears to be highly expressed in the cerebral cortex, hippocampus, thalamus and medulla oblongata. However, histological analyses revealed that Dpr2-/- mice had normal brain morphology; their neural stem cells showed proliferative activity similar to those of their wild-type littermates. Dpr2 was found to be highly expressed in epidermal keratinocytes and in hair follicles of adult mice, and its deficiency resulted in the accelerated re-epithelialization during cutaneous wound healing. Furthermore, loss of Dpr2 function enhanced the responses of keratinocytes to TGF-βstimulation; and TGF-βsignals promoted keratinocytes migration by regulating the expression of specific integrin genes.
Taken together, these data suggest that Dpr2 is dispensable for mouse embryonic development, postnatal growth and brain formation. But, Dpr2 plays an inhibitory role in the re-epithelialization of adult skin wounds by attenuating TGF-βsignaling.
目前,在小鼠中已发现三种Dpr家族成员,Dpr1-Dpr3。通过对他们时空表达谱的研究发现,三种Dpr均在胚胎的各时期表达,在成年组织的表达略有差异,但是在脑中的表达量都比较高。已有研究发现斑马鱼Dpr2通过促进Nodal/TGF-β的I型受体经溶酶体途径降解来调节其信号通路,体内功能实验证明斑马鱼Dpr2抑制Nodal信号的中胚层诱导活性。虽然小鼠Dpr2在体外能够抑制TGF-β信号,并且在斑马鱼胚胎中过表达也能减少一些中胚层特异基因的表达,但是关于小鼠Dpr2体内功能的研究还没有报道。
在本研究中,通过基因打靶技术制备了Dpr2基因完全敲除小鼠(Dpr2-/-)。但是却发现Dpr2-/-小鼠胚胎发育正常,并没有出现胚胎致死的表型。Dpr2-/-小鼠的囊胚同野生型的一样,可以从透明带中孵出并且拥有正常的Outgrowth。出生后的Dpr2-/-小鼠能够正常生长,雌雄均可育。对Dpr2-/-小鼠脑进行组织学分析没有发现任何异常,其神经干细胞的增殖同野生型小鼠也没有差别。本研究还发现Dpr2在成年小鼠的表皮及毛囊角质细胞中高表达,并且缺失Dpr2导致小鼠皮肤创伤愈合的再表皮化加快。进一步的研究证实,缺失Dpr2增强了角质细胞对TGF-β信号的反应性,并且TGF-β信号通过上调特定的integrin基因的表达来促进角质细胞的迁移。
由此可以得出如下结论:缺失Dpr2基因对于小鼠胚胎发育、生长和脑的形态没有影响,Dpr2通过抑制TGF-β信号来抑制创伤皮肤的再表皮化。
Transforming growth factor (TGF-β) signals regulate a variety of cellular events and play important roles in embryonic development. Members of the Dapper (Dpr)/Dact family play roles in regulating distinct signaling pathways, including TGF-β/Nodal as well as canonical and noncanonical Wnt pathways. Three mouse Dpr genes, Dpr1-Dpr3, are expressed in mouse embryos and in distinct adult tissues, particularly in the brain. It has been demonstrated that zebrafish Dpr2 modulates Nodal/TGF-βsignals by promoting lysosomal degradation of their receptors and inhibits mesoderm induction in zebrafish embryos. Mouse Dpr2 is able to antagonize TGF-β? signaling in vitro and ectopic expression in zebrafish embryos also results in reduction of mesoderm gene expression. However, functions of mDpr2 in vivo have not been reported.
In this study, Dpr2-deficient mice were generated by gene knockout approach. Dpr2 knockout (Dpr2-/-) embryos developed normally and they were alive at birth. Like wild-type blastocysts, the isolated Dpr2-/- E3.5 blastocysts hatched from the zona pellucida, and had normal Outgrowth. Postnatal Dpr2-/- mice were able to grow up and the adults were fertile. The distribution of Dpr2 transcripts in subregions of adult brain of mice was examined in details. Dpr2 appears to be highly expressed in the cerebral cortex, hippocampus, thalamus and medulla oblongata. However, histological analyses revealed that Dpr2-/- mice had normal brain morphology; their neural stem cells showed proliferative activity similar to those of their wild-type littermates. Dpr2 was found to be highly expressed in epidermal keratinocytes and in hair follicles of adult mice, and its deficiency resulted in the accelerated re-epithelialization during cutaneous wound healing. Furthermore, loss of Dpr2 function enhanced the responses of keratinocytes to TGF-βstimulation; and TGF-βsignals promoted keratinocytes migration by regulating the expression of specific integrin genes.
Taken together, these data suggest that Dpr2 is dispensable for mouse embryonic development, postnatal growth and brain formation. But, Dpr2 plays an inhibitory role in the re-epithelialization of adult skin wounds by attenuating TGF-βsignaling.
引文
[1] Massague, J., Blain, S.W. and Lo, R.S. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell, 2000, 103 (2): 295-309
[2] Schier, A.F. Nodal signaling in vertebrate development. Annu Rev Cell Dev Biol, 2003, 19: 589-621
[3] Tian, T. and Meng, A.M. Nodal signals pattern vertebrate embryos. Cell Mol Life Sci, 2006, 63 (6): 672-85
[4] Marikawa, Y. Wnt/beta-catenin signaling and body plan formation in mouse embryos. Semin Cell Dev Biol, 2006, 17 (2): 175-84
[5] Bottcher, R.T. and Niehrs, C. Fibroblast growth factor signaling during early vertebrate development. Endocr Rev, 2005, 26 (1): 63-77
[6] Cheyette, B.N., Waxman, J.S., Miller, J.R. et al. Dapper, a Dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation. Dev Cell, 2002, 2 (4): 449-61
[7] Zhang, L., Zhou, H., Su, Y. et al. Zebrafish Dpr2 inhibits mesoderm induction by promoting degradation of nodal receptors. Science, 2004, 306 (5693): 114-7
[8] Fleming, T.P. A quantitative analysis of cell allocation to trophectoderm and inner cell mass in the mouse blastocyst. Dev Biol, 1987, 119 (2): 520-31
[9] Johnson, M.H. and Ziomek, C.A. The foundation of two distinct cell lineages within the mouse morula. Cell, 1981, 24 (1): 71-80
[10] Evans, M.J. and Kaufman, M.H. Establishment in culture of pluripotential cells from mouse embryos. Nature, 1981, 292 (5819): 154-6
[11] Tanaka, S., Kunath, T., Hadjantonakis, A.K. et al. Promotion of trophoblast stem cell proliferation by FGF4. Science, 1998, 282 (5396): 2072-5
[12] Ralston, A. and Rossant, J. Genetic regulation of stem cell origins in the mouse embryo. Clin Genet, 2005, 68 (2): 106-12
[13] Barcroft, L.C., Offenberg, H., Thomsen, P. et al. Aquaporin proteins in murine trophectoderm mediate transepithelial water movements during cavitation. Dev Biol, 2003, 256 (2): 342-54
[14] Kunath, T., Arnaud, D., Uy, G.D. et al. Imprinted X-inactivation in extra-embryonic endoderm cell lines from mouse blastocysts. Development, 2005, 132 (7): 1649-61
[15] Srinivas, S., Rodriguez, T., Clements, M. et al. Active cell migration drives the unilateral movements of the anterior visceral endoderm. Development, 2004, 131 (5): 1157-64
[16] Thomas, P. and Beddington, R. Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo. Curr Biol, 1996, 6 (11): 1487-96
[17] Tam, P.P. and Steiner, K.A. Anterior patterning by synergistic activity of the early gastrula organizer and the anterior germ layer tissues of the mouse embryo. Development, 1999, 126 (22): 5171-9
[18] Beddington, R.S. and Robertson, E.J. Axis development and early asymmetry in mammals. Cell, 1999, 96 (2): 195-209
[19] Beddington, R.S. Induction of a second neural axis by the mouse node. Development, 1994, 120 (3): 613-20
[20] Bei, M. and Maas, R. FGFs and BMP4 induce both Msx1-independent and Msx1-dependent signaling pathways in early tooth development. Development, 1998, 125 (21): 4325-33
[21] Conlon, I. and Raff, M. Size control in animal development. Cell, 1999, 96 (2): 235-44
[22] Ducy, P., Starbuck, M., Priemel, M. et al. A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development. Genes Dev, 1999, 13 (8): 1025-36
[23] Burt, D.W. and Law, A.S. Evolution of the transforming growth factor-beta superfamily. Prog Growth Factor Res, 1994, 5 (1): 99-118
[24] Massague, J. The transforming growth factor-beta family. Annu Rev Cell Biol, 1990, 6: 597-641
[25] Feng, X.H. and Derynck, R. Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol, 2005, 21: 659-93
[26] Khalil, N. TGF-beta: from latent to active. Microbes Infect, 1999, 1 (15): 1255-63
[27] Massague, J. and Chen, Y.G. Controlling TGF-beta signaling. Genes Dev, 2000, 14 (6): 627-44
[28] Lin, H.Y., Wang, X.F., Ng-Eaton, E. et al. Expression cloning of the TGF-beta type II receptor, a functional transmembrane serine/threonine kinase. Cell, 1992, 68 (4): 775-85
[29] Lawler, S., Candia, A.F., Ebner, R. et al. The murine type II TGF-beta receptor has a coincident embryonic expression and binding preference for TGF-beta 1. Development, 1994, 120 (1): 165-75
[30] Wieser, R., Wrana, J.L. and Massague, J. GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex. EMBO J, 1995, 14 (10): 2199-208
[31] Wrana, J.L., Attisano, L., Wieser, R. et al. Mechanism of activation of the TGF-beta receptor. Nature, 1994, 370 (6488): 341-7
[32] Massague, J., Seoane, J. and Wotton, D. Smad transcription factors. Genes Dev, 2005, 19 (23): 2783-810
[33] Wrana, J.L. and Attisano, L. The Smad pathway. Cytokine Growth Factor Rev, 2000, 11 (1-2): 5-13
[34] Feng, X.H., Zhang, Y., Wu, R.Y. et al. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation. Genes Dev, 1998, 12 (14): 2153-63
[35] Akiyoshi, S., Inoue, H., Hanai, J. et al. c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads. J Biol Chem, 1999, 274 (49): 35269-77
[36] Sun, Y., Liu, X., Eaton, E.N. et al. Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signaling. Mol Cell, 1999, 4 (4): 499-509
[37] Massague, J. TGFbeta signaling: receptors, transducers, and Mad proteins. Cell, 1996, 85 (7): 947-50
[38] Wrana, J.L., Attisano, L., Carcamo, J. et al. TGF beta signals through a heteromeric protein kinase receptor complex. Cell, 1992, 71 (6): 1003-14
[39] Massague, J. TGF-beta signal transduction. Annu Rev Biochem, 1998, 67: 753-91
[40] Heldin, C.H., Miyazono, K. and ten Dijke, P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature, 1997, 390 (6659): 465-71
[41] Dickson, M.C., Martin, J.S., Cousins, F.M. et al. Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development, 1995, 121 (6): 1845-54
[42] Oshima, M., Oshima, H. and Taketo, M.M. TGF-beta receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev Biol, 1996, 179 (1): 297-302
[43] Oh, S.P., Seki, T., Goss, K.A. et al. Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A, 2000, 97 (6): 2626-31
[44] Urness, L.D., Sorensen, L.K. and Li, D.Y. Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet, 2000, 26 (3): 328-31
[45] Larsson, J., Goumans, M.J., Sjostrand, L.J. et al. Abnormal angiogenesis but intact hematopoietic potential in TGF-beta type I receptor-deficient mice. EMBO J, 2001, 20 (7): 1663-73
[46] Lechleider, R.J., Ryan, J.L., Garrett, L. et al. Targeted mutagenesis of Smad1 reveals an essential role in chorioallantoic fusion. Dev Biol, 2001, 240 (1): 157-67
[47] Weisberg, E., Winnier, G.E., Chen, X. et al. A mouse homologue of FAST-1 transduces TGF beta superfamily signals and is expressed during early embryogenesis. Mech Dev, 1998, 79 (1-2): 17-27
[48] Nomura, M. and Li, E. Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature, 1998, 393 (6687): 786-90
[49] Waldrip, W.R., Bikoff, E.K., Hoodless, P.A. et al. Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo. Cell, 1998, 92 (6): 797-808
[50] Sirard, C., de la Pompa, J.L., Elia, A. et al. The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo. Genes Dev, 1998, 12 (1): 107-19
[51] Yang, X., Li, C., Xu, X. et al. The tumor suppressor SMAD4/DPC4 is essential for epiblast proliferation and mesoderm induction in mice. Proc Natl Acad Sci U S A, 1998, 95 (7): 3667-72
[52] Chang, H., Huylebroeck, D., Verschueren, K. et al. Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects. Development, 1999, 126 (8): 1631-42
[53] Yang, X., Castilla, L.H., Xu, X. et al. Angiogenesis defects and mesenchymal apoptosis in mice lacking SMAD5. Development, 1999, 126 (8): 1571-80
[54] Yang, X., Chen, L., Xu, X. et al. TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol, 2001, 153 (1): 35-46
[55] Yang, X., Letterio, J.J., Lechleider, R.J. et al. Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. EMBO J, 1999, 18 (5): 1280-91
[56] Lopez-Gracia, M.L. and Ros, M.A. Left-right asymmetry in vertebrate development. Adv Anat Embryol Cell Biol, 2007, 188: 1-121, back cover
[57] Gritsman, K., Talbot, W.S. and Schier, A.F. Nodal signaling patterns the organizer. Development, 2000, 127 (5): 921-32
[58] Shi, Y. and Massague, J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell, 2003, 113 (6): 685-700
[59] Alexander, J. and Stainier, D.Y. A molecular pathway leading to endoderm formation in zebrafish. Curr Biol, 1999, 9 (20): 1147-57
[60] Jones, C.M., Kuehn, M.R., Hogan, B.L. et al. Nodal-related signals induce axial mesoderm and dorsalize mesoderm during gastrulation. Development, 1995, 121 (11): 3651-62
[61] Armes, N.A. and Smith, J.C. The ALK-2 and ALK-4 activin receptors transduce distinct mesoderm-inducing signals during early Xenopus development but do not co-operate to establish thresholds. Development, 1997, 124 (19): 3797-804
[62] Sakuma, R., Ohnishi Yi, Y., Meno, C. et al. Inhibition of Nodal signalling by Lefty mediated through interaction with common receptors and efficient diffusion. Genes Cells, 2002, 7 (4): 401-12
[63] Reissmann, E., Jornvall, H., Blokzijl, A. et al. The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development. Genes Dev, 2001, 15 (15): 2010-22
[64] Chang, C., Wilson, P.A., Mathews, L.S. et al. A Xenopus type I activin receptor mediates mesodermal but not neural specification during embryogenesis. Development, 1997, 124 (4): 827-37
[65] Gu, Z., Nomura, M., Simpson, B.B. et al. The type I activin receptor ActRIB is required for egg cylinder organization and gastrulation in the mouse. Genes Dev, 1998, 12 (6): 844-57
[66] Conlon, F.L., Lyons, K.M., Takaesu, N. et al. A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development, 1994, 120 (7): 1919-28
[67] Munir, S., Xu, G., Wu, Y. et al. Nodal and ALK7 inhibit proliferation and induce apoptosis in human trophoblast cells. J Biol Chem, 2004, 279 (30): 31277-86
[68] Jornvall, H., Reissmann, E., Andersson, O. et al. ALK7, a receptor for nodal, is dispensable for embryogenesis and left-right patterning in the mouse. Mol Cell Biol, 2004, 24 (21): 9383-9
[69] Oh, S.P. and Li, E. The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev, 1997, 11 (14): 1812-26
[70] Iannaccone, P.M., Zhou, X., Khokha, M. et al. Insertional mutation of a gene involved in growth regulation of the early mouse embryo. Dev Dyn, 1992, 194 (3): 198-208
[71] Yeo, C. and Whitman, M. Nodal signals to Smads through Cripto-dependent and Cripto-independent mechanisms. Mol Cell, 2001, 7 (5): 949-57
[72] Shiratori, H. and Hamada, H. The left-right axis in the mouse: from origin to morphology. Development, 2006, 133 (11): 2095-104
[73] Belo, J.A., Bouwmeester, T., Leyns, L. et al. Cerberus-like is a secreted factor with neutralizing activity expressed in the anterior primitive endoderm of the mouse gastrula. Mech Dev, 1997, 68 (1-2): 45-57
[74] Biben, C., Stanley, E., Fabri, L. et al. Murine cerberus homologue mCer-1: a candidate anterior patterning molecule. Dev Biol, 1998, 194 (2): 135-51
[75] Shawlot, W., Deng, J.M. and Behringer, R.R. Expression of the mouse cerberus-related gene, Cerr1, suggests a role in anterior neural induction and somitogenesis. Proc Natl Acad Sci U S A, 1998, 95 (11): 6198-203
[76] Meno, C., Gritsman, K., Ohishi, S. et al. Mouse Lefty2 and zebrafish antivin are feedback inhibitors of nodal signaling during vertebrate gastrulation. Mol Cell, 1999, 4 (3): 287-98
[77] Meno, C., Ito, Y., Saijoh, Y. et al. Two closely-related left-right asymmetrically expressed genes, lefty-1 and lefty-2: their distinct expression domains, chromosomal linkage and direct neuralizing activity in Xenopus embryos. Genes Cells, 1997, 2 (8): 513-24
[78] Meno, C., Saijoh, Y., Fujii, H. et al. Left-right asymmetric expression of the TGF beta-family member lefty in mouse embryos. Nature, 1996, 381 (6578): 151-5
[79] Meno, C., Shimono, A., Saijoh, Y. et al. lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Cell, 1998, 94 (3): 287-97
[80] Meno, C., Takeuchi, J., Sakuma, R. et al. Diffusion of nodal signaling activity in the absence of the feedback inhibitor Lefty2. Dev Cell, 2001, 1 (1): 127-38
[81] Yamamoto, M., Saijoh, Y., Perea-Gomez, A. et al. Nodal antagonists regulate formation of the anteroposterior axis of the mouse embryo. Nature, 2004, 428 (6981): 387-92
[82] Cadigan, K.M. and Nusse, R. Wnt signaling: a common theme in animal development. Genes Dev, 1997, 11 (24): 3286-305
[83] Heasman, J., Crawford, A., Goldstone, K. et al. Overexpression of cadherins and underexpression of beta-catenin inhibit dorsal mesoderm induction in early Xenopus embryos. Cell, 1994, 79 (5): 791-803
[84] Schneider, S., Steinbeisser, H., Warga, R.M. et al. Beta-catenin translocation into nuclei demarcates the dorsalizing centers in frog and fish embryos. Mech Dev, 1996, 57 (2): 191-8
[85] Pelegri, F. and Maischein, H.M. Function of zebrafish beta-catenin and TCF-3 in dorsoventral patterning. Mech Dev, 1998, 77 (1): 63-74
[86] Wikramanayake, A.H., Hong, M., Lee, P.N. et al. An ancient role for nuclear beta-catenin in the evolution of axial polarity and germ layer segregation. Nature, 2003, 426 (6965): 446-50
[87] Thorpe, C.J., Schlesinger, A., Carter, J.C. et al. Wnt signaling polarizes an early C. elegans blastomere to distinguish endoderm from mesoderm. Cell, 1997, 90 (4): 695-705
[88] Morin, P.J. beta-catenin signaling and cancer. Bioessays, 1999, 21 (12): 1021-30
[89] Cadigan, K.M. Wnt signaling--20 years and counting. Trends Genet, 2002, 18 (7): 340-2
[90] Giles, R.H., van Es, J.H. and Clevers, H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta, 2003, 1653 (1): 1-24
[91] Huelsken, J. and Behrens, J. The Wnt signalling pathway. J Cell Sci, 2002, 115 (Pt 21): 3977-8
[92] Hlsken, J. and Behrens, J. The Wnt signalling pathway. J Cell Sci, 2000, 113 ( Pt 20): 3545
[93] Hamatani, T., Carter, M.G., Sharov, A.A. et al. Dynamics of global gene expression changes during mouse preimplantation development. Dev Cell, 2004, 6 (1): 117-31
[94] Wang, Q.T., Piotrowska, K., Ciemerych, M.A. et al. A genome-wide study of gene activity reveals developmental signaling pathways in the preimplantation mouse embryo. Dev Cell, 2004, 6 (1): 133-44
[95] Huelsken, J., Vogel, R., Brinkmann, V. et al. Requirement for beta-catenin in anterior-posterior axis formation in mice. J Cell Biol, 2000, 148 (3): 567-78
[96] Barrow, J.R., Thomas, K.R., Boussadia-Zahui, O. et al. Ectodermal Wnt3/beta-catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge. Genes Dev, 2003, 17 (3): 394-409
[97] Muller, U. Ten years of gene targeting: targeted mouse mutants, from vector design to phenotype analysis. Mech Dev, 1999, 82 (1-2): 3-21
[98] Sikorski, R. and Peters, R. Transgenics on the Internet. Nat Biotechnol, 1997, 15 (3): 289
[99] Royden, C.S., Pirrotta, V. and Jan, L.Y. The tko locus, site of a behavioral mutation in D. melanogaster, codes for a protein homologous to prokaryotic ribosomal protein S12. Cell, 1987, 51 (2): 165-73
[100] Gu, H., Marth, J.D., Orban, P.C. et al. Deletion of a DNA polymerase beta gene segment in T cells using cell type-specific gene targeting. Science, 1994, 265 (5168): 103-6
[101] Lakso, M., Pichel, J.G., Gorman, J.R. et al. Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. Proc Natl Acad Sci U S A, 1996, 93 (12): 5860-5
[102] Xu, X., Qiao, W., Li, C. et al. Generation of Fgfr1 conditional knockout mice. Genesis, 2002, 32 (2): 85-6
[103] Zhang, P., Li, M.Z. and Elledge, S.J. Towards genetic genome projects: genomic library screening and gene-targeting vector construction in a single step. Nat Genet, 2002, 30 (1): 31-9
[104] Kuhn, R., Schwenk, F., Aguet, M. et al. Inducible gene targeting in mice. Science, 1995, 269 (5229): 1427-9
[105] Schwenk, F., Kuhn, R., Angrand, P.O. et al. Temporally and spatially regulated somatic mutagenesis in mice. Nucleic Acids Res, 1998, 26 (6): 1427-32
[106] Thomas, K.R. and Capecchi, M.R. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell, 1987, 51 (3): 503-12
[107] Zimmer, A. and Gruss, P. Production of chimaeric mice containing embryonic stem (ES) cells carrying a homoeobox Hox 1.1 allele mutated by homologous recombination. Nature, 1989, 338 (6211): 150-3
[108] Schafer, M. and Werner, S. Transcriptional control of wound repair. Annu Rev Cell Dev Biol, 2007, 23: 69-92
[109] Singer, A.J. and Clark, R.A. Cutaneous wound healing. N Engl J Med, 1999, 341 (10): 738-46
[110] Ito, M., Liu, Y., Yang, Z. et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med, 2005, 11 (12): 1351-4
[111] Santoro, M.M. and Gaudino, G. Cellular and molecular facets of keratinocyte reepithelization during wound healing. Exp Cell Res, 2005, 304 (1): 274-86
[112] Grose, R. and Werner, S. Wound-healing studies in transgenic and knockout mice. Mol Biotechnol, 2004, 28 (2): 147-66
[113] Hosokawa, R., Urata, M.M., Ito, Y. et al. Functional significance of Smad2 in regulating basal keratinocyte migration during wound healing. J Invest Dermatol, 2005, 125 (6): 1302-9
[114] Amendt, C., Mann, A., Schirmacher, P. et al. Resistance of keratinocytes to TGFbeta-mediated growth restriction and apoptosis induction accelerates re-epithelialization in skin wounds. J Cell Sci, 2002, 115 (Pt 10): 2189-98
[115] Brown, R.L., Ormsby, I., Doetschman, T.C. et al. Wound healing in the transforming growth factor-beta-deficient mouse. Wound Repair Regen, 1995, 3 (1): 25-36
[116] Shah, M., Revis, D., Herrick, S. et al. Role of elevated plasma transforming growth factor-beta1 levels in wound healing. Am J Pathol, 1999, 154 (4): 1115-24
[117] Crowe, M.J., Doetschman, T. and Greenhalgh, D.G. Delayed wound healing in immunodeficient TGF-beta 1 knockout mice. J Invest Dermatol, 2000, 115 (1): 3-11
[118] Jeong, H.W. and Kim, I.S. TGF-beta1 enhances betaig-h3-mediated keratinocyte cell migration through the alpha3beta1 integrin and PI3K. J Cell Biochem, 2004, 92 (4): 770-80
[119] Tredget, E.B., Demare, J., Chandran, G. et al. Transforming growth factor-beta and its effect on reepithelialization of partial-thickness ear wounds in transgenic mice. Wound Repair Regen, 2005, 13 (1): 61-7
[120] Reynolds, L.E., Conti, F.J., Lucas, M. et al. Accelerated re-epithelialization in beta3-integrin-deficient- mice is associated with enhanced TGF-beta1 signaling. Nat Med, 2005, 11 (2): 167-74
[121] Werner, S. and Grose, R. Regulation of wound healing by growth factors and cytokines. Physiol Rev, 2003, 83 (3): 835-70
[122] Hebda, P.A. Stimulatory effects of transforming growth factor-beta and epidermal growth factor on epidermal cell outgrowth from porcine skin explant cultures. J Invest Dermatol, 1988, 91 (5): 440-5
[123] Sellheyer, K., Bickenbach, J.R., Rothnagel, J.A. et al. Inhibition of skin development by overexpression of transforming growth factor beta 1 in the epidermis of transgenic mice. Proc Natl Acad Sci U S A, 1993, 90 (11): 5237-41
[124] Yang, L., Mao, C., Teng, Y. et al. Targeted disruption of Smad4 in mouse epidermis results in failure of hair follicle cycling and formation of skin tumors. Cancer Res, 2005, 65 (19): 8671-8
[125] Ashcroft, G.S., Yang, X., Glick, A.B. et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol, 1999, 1 (5): 260-6
[126] Chan, T., Ghahary, A., Demare, J. et al. Development, characterization, and wound healing of the keratin 14 promoted transforming growth factor-beta1 transgenic mouse. Wound Repair Regen, 2002, 10 (3): 177-87
[127] Yang, L., Chan, T., Demare, J. et al. Healing of burn wounds in transgenic mice overexpressing transforming growth factor-beta 1 in the epidermis. Am J Pathol, 2001, 159 (6): 2147-57
[128] Gloy, J., Hikasa, H. and Sokol, S.Y. Frodo interacts with Dishevelled to transduce Wnt signals. Nat Cell Biol, 2002, 4 (5): 351-7
[129] Katoh, M. and Katoh, M. Identification and characterization of human DAPPER1 and DAPPER2 genes in silico. Int J Oncol, 2003, 22 (4): 907-13
[130] Katoh, M. and Katoh, M. Identification and characterization of rat Dact1 and Dact2 genes in silico. Int J Mol Med, 2005, 15 (6): 1045-9
[131] Zhang, L., Gao, X., Wen, J. et al. Dapper 1 antagonizes Wnt signaling by promoting dishevelled degradation. J Biol Chem, 2006, 281 (13): 8607-12
[132] Yau, T.O., Chan, C.Y., Chan, K.L. et al. HDPR1, a novel inhibitor of the WNT/beta-catenin signaling, is frequently downregulated in hepatocellular carcinoma: involvement of methylation-mediated gene silencing. Oncogene, 2005, 24 (9): 1607-14
[133] Waxman, J.S., Hocking, A.M., Stoick, C.L. et al. Zebrafish Dapper1 and Dapper2 play distinct roles in Wnt-mediated developmental processes. Development, 2004, 131 (23): 5909-21
[134] Fisher, D.A., Kivimae, S., Hoshino, J. et al. Three Dact gene family members are expressed during embryonic development and in the adult brains of mice. Dev Dyn, 2006, 235 (9): 2620-30
[135] Wong, H.C., Bourdelas, A., Krauss, A. et al. Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled. Mol Cell, 2003, 12 (5): 1251-60
[136] Brott, B.K. and Sokol, S.Y. A vertebrate homolog of the cell cycle regulator Dbf4 is an inhibitor of Wnt signaling required for heart development. Dev Cell, 2005, 8 (5): 703-15
[137] Su, Y., Zhang, L., Gao, X. et al. The evolutionally conserved activity of Dapper2 in antagonizing TGF-beta signaling. FASEB J, 2007, 21 (3): 682-90
[138] Brott, B.K. and Sokol, S.Y. Frodo proteins: modulators of Wnt signaling in vertebrate development. Differentiation, 2005, 73 (7): 323-9
[139] Gillhouse, M., Wagner Nyholm, M., Hikasa, H. et al. Two Frodo/Dapper homologs are expressed in the developing brain and mesoderm of zebrafish. Dev Dyn, 2004, 230 (3): 403-9
[140] Deng, C.X., Wynshaw-Boris, A., Shen, M.M. et al. Murine FGFR-1 is required for early postimplantation growth and axial organization. Genes Dev, 1994, 8 (24): 3045-57
[141] Sage, J., Mulligan, G.J., Attardi, L.D. et al. Targeted disruption of the three Rb-related genes leads to loss of G(1) control and immortalization. Genes Dev, 2000, 14 (23): 3037-50
[142] Stepp, M.A., Liu, Y., Pal-Ghosh, S. et al. Reduced migration, altered matrix and enhanced TGFbeta1 signaling are signatures of mouse keratinocytes lacking Sdc1. J Cell Sci, 2007, 120 (Pt 16): 2851-63
[143] Brody, D.L. and Holtzman, D.M. Morris water maze search strategy analysis in PDAPP mice before and after experimental traumatic brain injury. Exp Neurol, 2006, 197 (2): 330-40
[144] Huang, F.L., Huang, K.P., Wu, J. et al. Environmental enrichment enhances neurogranin expression and hippocampal learning and memory but fails to rescue the impairments of neurogranin null mutant mice. J Neurosci, 2006, 26 (23): 6230-7
[145] Teixeira, C.M., Pomedli, S.R., Maei, H.R. et al. Involvement of the anterior cingulate cortex in the expression of remote spatial memory. J Neurosci, 2006, 26 (29): 7555-64
[146] Zhang, C., Meng, F., Wang, C. et al. Identification of a novel alternative splicing form of human netrin-4 and analyzing the expression patterns in adult rat brain. Brain Res Mol Brain Res, 2004, 130 (1-2): 68-80
[147] Vassar, R., Rosenberg, M., Ross, S. et al. Tissue-specific and differentiation-specific expression of a human K14 keratin gene in transgenic mice. Proc Natl Acad Sci U S A, 1989, 86 (5): 1563-7
[148] Gat, U., DasGupta, R., Degenstein, L. et al. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell, 1998, 95 (5): 605-14
[149] Li, T., Inoue, A., Lahti, J.M. et al. Failure to proliferate and mitotic arrest of CDK11(p110/p58)-null mutant mice at the blastocyst stage of embryonic cell development. Mol Cell Biol, 2004, 24 (8): 3188-97
[150] Van Eynde, A., Nuytten, M., Dewerchin, M. et al. The nuclear scaffold protein NIPP1 is essential for early embryonic development and cell proliferation. Mol Cell Biol, 2004, 24 (13): 5863-74
[151] Luskin, M.B. Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron, 1993, 11 (1): 173-89
[152] Alvarez-Buylla, A. and Garcia-Verdugo, J.M. Neurogenesis in adult subventricular zone. J Neurosci, 2002, 22 (3): 629-34
[153] Taupin, P. Neural progenitor and stem cells in the adult central nervous system. Ann Acad Med Singapore, 2006, 35 (11): 814-20
[154] Barrow, J.R. Wnt/PCP signaling: a veritable polar star in establishing patterns of polarity in embryonic tissues. Semin Cell Dev Biol, 2006, 17 (2): 185-93
[155] Laping, N.J., Grygielko, E., Mathur, A. et al. Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542. Mol Pharmacol, 2002, 62 (1): 58-64
[156] Steffensen, B., Hakkinen, L. and Larjava, H. Proteolytic events of wound-healing--coordinated interactions among matrix metalloproteinases (MMPs), integrins, and extracellular matrix molecules. Crit Rev Oral Biol Med, 2001, 12 (5): 373-98
[157] Juhasz, I., Murphy, G.F., Yan, H.C. et al. Regulation of extracellular matrix proteins and integrin cell substratum adhesion receptors on epithelium during cutaneous human wound healing in vivo. Am J Pathol, 1993, 143 (5): 1458-69
[158] Zambruno, G., Marchisio, P.C., Marconi, A. et al. Transforming growth factor-beta 1 modulates beta 1 and beta 5 integrin receptors and induces the de novo expression of the alpha v beta 6 heterodimer in normal human keratinocytes: implications for wound healing. J Cell Biol, 1995, 129 (3): 853-65
[159] Martin, P. Wound healing--aiming for perfect skin regeneration. Science, 1997, 276 (5309): 75-81
[160] Grose, R., Hutter, C., Bloch, W. et al. A crucial role of beta 1 integrins for keratinocyte migration in vitro and during cutaneous wound repair. Development, 2002, 129 (9): 2303-15
[161] Gailit, J., Welch, M.P. and Clark, R.A. TGF-beta 1 stimulates expression of keratinocyte integrins during re-epithelialization of cutaneous wounds. J Invest Dermatol, 1994, 103 (2): 221-7
[162] Garlick, J.A. and Taichman, L.B. Fate of human keratinocytes during reepithelialization in an organotypic culture model. Lab Invest, 1994, 70 (6): 916-24
[163] Larjava, H., Salo, T., Haapasalmi, K. et al. Expression of integrins and basement membrane components by wound keratinocytes. J Clin Invest, 1993, 92 (3): 1425-35
[164] Hynes, R.O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell, 1992, 69 (1): 11-25
[165] Weinacker, A., Chen, A., Agrez, M. et al. Role of the integrin alpha v beta 6 in cell attachment to fibronectin. Heterologous expression of intact and secreted forms of the receptor. J Biol Chem, 1994, 269 (9): 6940-8
[166] Huang, X., Wu, J., Spong, S. et al. The integrin alphavbeta6 is critical for keratinocyte migration on both its known ligand, fibronectin, and on vitronectin. J Cell Sci, 1998, 111 ( Pt 15): 2189-95
[167] Thomas, G.J., Poomsawat, S., Lewis, M.P. et al. alpha v beta 6 Integrin upregulates matrix metalloproteinase 9 and promotes migration of normal oral keratinocytes. J Invest Dermatol, 2001, 116 (6): 898-904
[2] Schier, A.F. Nodal signaling in vertebrate development. Annu Rev Cell Dev Biol, 2003, 19: 589-621
[3] Tian, T. and Meng, A.M. Nodal signals pattern vertebrate embryos. Cell Mol Life Sci, 2006, 63 (6): 672-85
[4] Marikawa, Y. Wnt/beta-catenin signaling and body plan formation in mouse embryos. Semin Cell Dev Biol, 2006, 17 (2): 175-84
[5] Bottcher, R.T. and Niehrs, C. Fibroblast growth factor signaling during early vertebrate development. Endocr Rev, 2005, 26 (1): 63-77
[6] Cheyette, B.N., Waxman, J.S., Miller, J.R. et al. Dapper, a Dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation. Dev Cell, 2002, 2 (4): 449-61
[7] Zhang, L., Zhou, H., Su, Y. et al. Zebrafish Dpr2 inhibits mesoderm induction by promoting degradation of nodal receptors. Science, 2004, 306 (5693): 114-7
[8] Fleming, T.P. A quantitative analysis of cell allocation to trophectoderm and inner cell mass in the mouse blastocyst. Dev Biol, 1987, 119 (2): 520-31
[9] Johnson, M.H. and Ziomek, C.A. The foundation of two distinct cell lineages within the mouse morula. Cell, 1981, 24 (1): 71-80
[10] Evans, M.J. and Kaufman, M.H. Establishment in culture of pluripotential cells from mouse embryos. Nature, 1981, 292 (5819): 154-6
[11] Tanaka, S., Kunath, T., Hadjantonakis, A.K. et al. Promotion of trophoblast stem cell proliferation by FGF4. Science, 1998, 282 (5396): 2072-5
[12] Ralston, A. and Rossant, J. Genetic regulation of stem cell origins in the mouse embryo. Clin Genet, 2005, 68 (2): 106-12
[13] Barcroft, L.C., Offenberg, H., Thomsen, P. et al. Aquaporin proteins in murine trophectoderm mediate transepithelial water movements during cavitation. Dev Biol, 2003, 256 (2): 342-54
[14] Kunath, T., Arnaud, D., Uy, G.D. et al. Imprinted X-inactivation in extra-embryonic endoderm cell lines from mouse blastocysts. Development, 2005, 132 (7): 1649-61
[15] Srinivas, S., Rodriguez, T., Clements, M. et al. Active cell migration drives the unilateral movements of the anterior visceral endoderm. Development, 2004, 131 (5): 1157-64
[16] Thomas, P. and Beddington, R. Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo. Curr Biol, 1996, 6 (11): 1487-96
[17] Tam, P.P. and Steiner, K.A. Anterior patterning by synergistic activity of the early gastrula organizer and the anterior germ layer tissues of the mouse embryo. Development, 1999, 126 (22): 5171-9
[18] Beddington, R.S. and Robertson, E.J. Axis development and early asymmetry in mammals. Cell, 1999, 96 (2): 195-209
[19] Beddington, R.S. Induction of a second neural axis by the mouse node. Development, 1994, 120 (3): 613-20
[20] Bei, M. and Maas, R. FGFs and BMP4 induce both Msx1-independent and Msx1-dependent signaling pathways in early tooth development. Development, 1998, 125 (21): 4325-33
[21] Conlon, I. and Raff, M. Size control in animal development. Cell, 1999, 96 (2): 235-44
[22] Ducy, P., Starbuck, M., Priemel, M. et al. A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development. Genes Dev, 1999, 13 (8): 1025-36
[23] Burt, D.W. and Law, A.S. Evolution of the transforming growth factor-beta superfamily. Prog Growth Factor Res, 1994, 5 (1): 99-118
[24] Massague, J. The transforming growth factor-beta family. Annu Rev Cell Biol, 1990, 6: 597-641
[25] Feng, X.H. and Derynck, R. Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol, 2005, 21: 659-93
[26] Khalil, N. TGF-beta: from latent to active. Microbes Infect, 1999, 1 (15): 1255-63
[27] Massague, J. and Chen, Y.G. Controlling TGF-beta signaling. Genes Dev, 2000, 14 (6): 627-44
[28] Lin, H.Y., Wang, X.F., Ng-Eaton, E. et al. Expression cloning of the TGF-beta type II receptor, a functional transmembrane serine/threonine kinase. Cell, 1992, 68 (4): 775-85
[29] Lawler, S., Candia, A.F., Ebner, R. et al. The murine type II TGF-beta receptor has a coincident embryonic expression and binding preference for TGF-beta 1. Development, 1994, 120 (1): 165-75
[30] Wieser, R., Wrana, J.L. and Massague, J. GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex. EMBO J, 1995, 14 (10): 2199-208
[31] Wrana, J.L., Attisano, L., Wieser, R. et al. Mechanism of activation of the TGF-beta receptor. Nature, 1994, 370 (6488): 341-7
[32] Massague, J., Seoane, J. and Wotton, D. Smad transcription factors. Genes Dev, 2005, 19 (23): 2783-810
[33] Wrana, J.L. and Attisano, L. The Smad pathway. Cytokine Growth Factor Rev, 2000, 11 (1-2): 5-13
[34] Feng, X.H., Zhang, Y., Wu, R.Y. et al. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation. Genes Dev, 1998, 12 (14): 2153-63
[35] Akiyoshi, S., Inoue, H., Hanai, J. et al. c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads. J Biol Chem, 1999, 274 (49): 35269-77
[36] Sun, Y., Liu, X., Eaton, E.N. et al. Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signaling. Mol Cell, 1999, 4 (4): 499-509
[37] Massague, J. TGFbeta signaling: receptors, transducers, and Mad proteins. Cell, 1996, 85 (7): 947-50
[38] Wrana, J.L., Attisano, L., Carcamo, J. et al. TGF beta signals through a heteromeric protein kinase receptor complex. Cell, 1992, 71 (6): 1003-14
[39] Massague, J. TGF-beta signal transduction. Annu Rev Biochem, 1998, 67: 753-91
[40] Heldin, C.H., Miyazono, K. and ten Dijke, P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature, 1997, 390 (6659): 465-71
[41] Dickson, M.C., Martin, J.S., Cousins, F.M. et al. Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development, 1995, 121 (6): 1845-54
[42] Oshima, M., Oshima, H. and Taketo, M.M. TGF-beta receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev Biol, 1996, 179 (1): 297-302
[43] Oh, S.P., Seki, T., Goss, K.A. et al. Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A, 2000, 97 (6): 2626-31
[44] Urness, L.D., Sorensen, L.K. and Li, D.Y. Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet, 2000, 26 (3): 328-31
[45] Larsson, J., Goumans, M.J., Sjostrand, L.J. et al. Abnormal angiogenesis but intact hematopoietic potential in TGF-beta type I receptor-deficient mice. EMBO J, 2001, 20 (7): 1663-73
[46] Lechleider, R.J., Ryan, J.L., Garrett, L. et al. Targeted mutagenesis of Smad1 reveals an essential role in chorioallantoic fusion. Dev Biol, 2001, 240 (1): 157-67
[47] Weisberg, E., Winnier, G.E., Chen, X. et al. A mouse homologue of FAST-1 transduces TGF beta superfamily signals and is expressed during early embryogenesis. Mech Dev, 1998, 79 (1-2): 17-27
[48] Nomura, M. and Li, E. Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature, 1998, 393 (6687): 786-90
[49] Waldrip, W.R., Bikoff, E.K., Hoodless, P.A. et al. Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo. Cell, 1998, 92 (6): 797-808
[50] Sirard, C., de la Pompa, J.L., Elia, A. et al. The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo. Genes Dev, 1998, 12 (1): 107-19
[51] Yang, X., Li, C., Xu, X. et al. The tumor suppressor SMAD4/DPC4 is essential for epiblast proliferation and mesoderm induction in mice. Proc Natl Acad Sci U S A, 1998, 95 (7): 3667-72
[52] Chang, H., Huylebroeck, D., Verschueren, K. et al. Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects. Development, 1999, 126 (8): 1631-42
[53] Yang, X., Castilla, L.H., Xu, X. et al. Angiogenesis defects and mesenchymal apoptosis in mice lacking SMAD5. Development, 1999, 126 (8): 1571-80
[54] Yang, X., Chen, L., Xu, X. et al. TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol, 2001, 153 (1): 35-46
[55] Yang, X., Letterio, J.J., Lechleider, R.J. et al. Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. EMBO J, 1999, 18 (5): 1280-91
[56] Lopez-Gracia, M.L. and Ros, M.A. Left-right asymmetry in vertebrate development. Adv Anat Embryol Cell Biol, 2007, 188: 1-121, back cover
[57] Gritsman, K., Talbot, W.S. and Schier, A.F. Nodal signaling patterns the organizer. Development, 2000, 127 (5): 921-32
[58] Shi, Y. and Massague, J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell, 2003, 113 (6): 685-700
[59] Alexander, J. and Stainier, D.Y. A molecular pathway leading to endoderm formation in zebrafish. Curr Biol, 1999, 9 (20): 1147-57
[60] Jones, C.M., Kuehn, M.R., Hogan, B.L. et al. Nodal-related signals induce axial mesoderm and dorsalize mesoderm during gastrulation. Development, 1995, 121 (11): 3651-62
[61] Armes, N.A. and Smith, J.C. The ALK-2 and ALK-4 activin receptors transduce distinct mesoderm-inducing signals during early Xenopus development but do not co-operate to establish thresholds. Development, 1997, 124 (19): 3797-804
[62] Sakuma, R., Ohnishi Yi, Y., Meno, C. et al. Inhibition of Nodal signalling by Lefty mediated through interaction with common receptors and efficient diffusion. Genes Cells, 2002, 7 (4): 401-12
[63] Reissmann, E., Jornvall, H., Blokzijl, A. et al. The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development. Genes Dev, 2001, 15 (15): 2010-22
[64] Chang, C., Wilson, P.A., Mathews, L.S. et al. A Xenopus type I activin receptor mediates mesodermal but not neural specification during embryogenesis. Development, 1997, 124 (4): 827-37
[65] Gu, Z., Nomura, M., Simpson, B.B. et al. The type I activin receptor ActRIB is required for egg cylinder organization and gastrulation in the mouse. Genes Dev, 1998, 12 (6): 844-57
[66] Conlon, F.L., Lyons, K.M., Takaesu, N. et al. A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development, 1994, 120 (7): 1919-28
[67] Munir, S., Xu, G., Wu, Y. et al. Nodal and ALK7 inhibit proliferation and induce apoptosis in human trophoblast cells. J Biol Chem, 2004, 279 (30): 31277-86
[68] Jornvall, H., Reissmann, E., Andersson, O. et al. ALK7, a receptor for nodal, is dispensable for embryogenesis and left-right patterning in the mouse. Mol Cell Biol, 2004, 24 (21): 9383-9
[69] Oh, S.P. and Li, E. The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev, 1997, 11 (14): 1812-26
[70] Iannaccone, P.M., Zhou, X., Khokha, M. et al. Insertional mutation of a gene involved in growth regulation of the early mouse embryo. Dev Dyn, 1992, 194 (3): 198-208
[71] Yeo, C. and Whitman, M. Nodal signals to Smads through Cripto-dependent and Cripto-independent mechanisms. Mol Cell, 2001, 7 (5): 949-57
[72] Shiratori, H. and Hamada, H. The left-right axis in the mouse: from origin to morphology. Development, 2006, 133 (11): 2095-104
[73] Belo, J.A., Bouwmeester, T., Leyns, L. et al. Cerberus-like is a secreted factor with neutralizing activity expressed in the anterior primitive endoderm of the mouse gastrula. Mech Dev, 1997, 68 (1-2): 45-57
[74] Biben, C., Stanley, E., Fabri, L. et al. Murine cerberus homologue mCer-1: a candidate anterior patterning molecule. Dev Biol, 1998, 194 (2): 135-51
[75] Shawlot, W., Deng, J.M. and Behringer, R.R. Expression of the mouse cerberus-related gene, Cerr1, suggests a role in anterior neural induction and somitogenesis. Proc Natl Acad Sci U S A, 1998, 95 (11): 6198-203
[76] Meno, C., Gritsman, K., Ohishi, S. et al. Mouse Lefty2 and zebrafish antivin are feedback inhibitors of nodal signaling during vertebrate gastrulation. Mol Cell, 1999, 4 (3): 287-98
[77] Meno, C., Ito, Y., Saijoh, Y. et al. Two closely-related left-right asymmetrically expressed genes, lefty-1 and lefty-2: their distinct expression domains, chromosomal linkage and direct neuralizing activity in Xenopus embryos. Genes Cells, 1997, 2 (8): 513-24
[78] Meno, C., Saijoh, Y., Fujii, H. et al. Left-right asymmetric expression of the TGF beta-family member lefty in mouse embryos. Nature, 1996, 381 (6578): 151-5
[79] Meno, C., Shimono, A., Saijoh, Y. et al. lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Cell, 1998, 94 (3): 287-97
[80] Meno, C., Takeuchi, J., Sakuma, R. et al. Diffusion of nodal signaling activity in the absence of the feedback inhibitor Lefty2. Dev Cell, 2001, 1 (1): 127-38
[81] Yamamoto, M., Saijoh, Y., Perea-Gomez, A. et al. Nodal antagonists regulate formation of the anteroposterior axis of the mouse embryo. Nature, 2004, 428 (6981): 387-92
[82] Cadigan, K.M. and Nusse, R. Wnt signaling: a common theme in animal development. Genes Dev, 1997, 11 (24): 3286-305
[83] Heasman, J., Crawford, A., Goldstone, K. et al. Overexpression of cadherins and underexpression of beta-catenin inhibit dorsal mesoderm induction in early Xenopus embryos. Cell, 1994, 79 (5): 791-803
[84] Schneider, S., Steinbeisser, H., Warga, R.M. et al. Beta-catenin translocation into nuclei demarcates the dorsalizing centers in frog and fish embryos. Mech Dev, 1996, 57 (2): 191-8
[85] Pelegri, F. and Maischein, H.M. Function of zebrafish beta-catenin and TCF-3 in dorsoventral patterning. Mech Dev, 1998, 77 (1): 63-74
[86] Wikramanayake, A.H., Hong, M., Lee, P.N. et al. An ancient role for nuclear beta-catenin in the evolution of axial polarity and germ layer segregation. Nature, 2003, 426 (6965): 446-50
[87] Thorpe, C.J., Schlesinger, A., Carter, J.C. et al. Wnt signaling polarizes an early C. elegans blastomere to distinguish endoderm from mesoderm. Cell, 1997, 90 (4): 695-705
[88] Morin, P.J. beta-catenin signaling and cancer. Bioessays, 1999, 21 (12): 1021-30
[89] Cadigan, K.M. Wnt signaling--20 years and counting. Trends Genet, 2002, 18 (7): 340-2
[90] Giles, R.H., van Es, J.H. and Clevers, H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta, 2003, 1653 (1): 1-24
[91] Huelsken, J. and Behrens, J. The Wnt signalling pathway. J Cell Sci, 2002, 115 (Pt 21): 3977-8
[92] Hlsken, J. and Behrens, J. The Wnt signalling pathway. J Cell Sci, 2000, 113 ( Pt 20): 3545
[93] Hamatani, T., Carter, M.G., Sharov, A.A. et al. Dynamics of global gene expression changes during mouse preimplantation development. Dev Cell, 2004, 6 (1): 117-31
[94] Wang, Q.T., Piotrowska, K., Ciemerych, M.A. et al. A genome-wide study of gene activity reveals developmental signaling pathways in the preimplantation mouse embryo. Dev Cell, 2004, 6 (1): 133-44
[95] Huelsken, J., Vogel, R., Brinkmann, V. et al. Requirement for beta-catenin in anterior-posterior axis formation in mice. J Cell Biol, 2000, 148 (3): 567-78
[96] Barrow, J.R., Thomas, K.R., Boussadia-Zahui, O. et al. Ectodermal Wnt3/beta-catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge. Genes Dev, 2003, 17 (3): 394-409
[97] Muller, U. Ten years of gene targeting: targeted mouse mutants, from vector design to phenotype analysis. Mech Dev, 1999, 82 (1-2): 3-21
[98] Sikorski, R. and Peters, R. Transgenics on the Internet. Nat Biotechnol, 1997, 15 (3): 289
[99] Royden, C.S., Pirrotta, V. and Jan, L.Y. The tko locus, site of a behavioral mutation in D. melanogaster, codes for a protein homologous to prokaryotic ribosomal protein S12. Cell, 1987, 51 (2): 165-73
[100] Gu, H., Marth, J.D., Orban, P.C. et al. Deletion of a DNA polymerase beta gene segment in T cells using cell type-specific gene targeting. Science, 1994, 265 (5168): 103-6
[101] Lakso, M., Pichel, J.G., Gorman, J.R. et al. Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. Proc Natl Acad Sci U S A, 1996, 93 (12): 5860-5
[102] Xu, X., Qiao, W., Li, C. et al. Generation of Fgfr1 conditional knockout mice. Genesis, 2002, 32 (2): 85-6
[103] Zhang, P., Li, M.Z. and Elledge, S.J. Towards genetic genome projects: genomic library screening and gene-targeting vector construction in a single step. Nat Genet, 2002, 30 (1): 31-9
[104] Kuhn, R., Schwenk, F., Aguet, M. et al. Inducible gene targeting in mice. Science, 1995, 269 (5229): 1427-9
[105] Schwenk, F., Kuhn, R., Angrand, P.O. et al. Temporally and spatially regulated somatic mutagenesis in mice. Nucleic Acids Res, 1998, 26 (6): 1427-32
[106] Thomas, K.R. and Capecchi, M.R. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell, 1987, 51 (3): 503-12
[107] Zimmer, A. and Gruss, P. Production of chimaeric mice containing embryonic stem (ES) cells carrying a homoeobox Hox 1.1 allele mutated by homologous recombination. Nature, 1989, 338 (6211): 150-3
[108] Schafer, M. and Werner, S. Transcriptional control of wound repair. Annu Rev Cell Dev Biol, 2007, 23: 69-92
[109] Singer, A.J. and Clark, R.A. Cutaneous wound healing. N Engl J Med, 1999, 341 (10): 738-46
[110] Ito, M., Liu, Y., Yang, Z. et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med, 2005, 11 (12): 1351-4
[111] Santoro, M.M. and Gaudino, G. Cellular and molecular facets of keratinocyte reepithelization during wound healing. Exp Cell Res, 2005, 304 (1): 274-86
[112] Grose, R. and Werner, S. Wound-healing studies in transgenic and knockout mice. Mol Biotechnol, 2004, 28 (2): 147-66
[113] Hosokawa, R., Urata, M.M., Ito, Y. et al. Functional significance of Smad2 in regulating basal keratinocyte migration during wound healing. J Invest Dermatol, 2005, 125 (6): 1302-9
[114] Amendt, C., Mann, A., Schirmacher, P. et al. Resistance of keratinocytes to TGFbeta-mediated growth restriction and apoptosis induction accelerates re-epithelialization in skin wounds. J Cell Sci, 2002, 115 (Pt 10): 2189-98
[115] Brown, R.L., Ormsby, I., Doetschman, T.C. et al. Wound healing in the transforming growth factor-beta-deficient mouse. Wound Repair Regen, 1995, 3 (1): 25-36
[116] Shah, M., Revis, D., Herrick, S. et al. Role of elevated plasma transforming growth factor-beta1 levels in wound healing. Am J Pathol, 1999, 154 (4): 1115-24
[117] Crowe, M.J., Doetschman, T. and Greenhalgh, D.G. Delayed wound healing in immunodeficient TGF-beta 1 knockout mice. J Invest Dermatol, 2000, 115 (1): 3-11
[118] Jeong, H.W. and Kim, I.S. TGF-beta1 enhances betaig-h3-mediated keratinocyte cell migration through the alpha3beta1 integrin and PI3K. J Cell Biochem, 2004, 92 (4): 770-80
[119] Tredget, E.B., Demare, J., Chandran, G. et al. Transforming growth factor-beta and its effect on reepithelialization of partial-thickness ear wounds in transgenic mice. Wound Repair Regen, 2005, 13 (1): 61-7
[120] Reynolds, L.E., Conti, F.J., Lucas, M. et al. Accelerated re-epithelialization in beta3-integrin-deficient- mice is associated with enhanced TGF-beta1 signaling. Nat Med, 2005, 11 (2): 167-74
[121] Werner, S. and Grose, R. Regulation of wound healing by growth factors and cytokines. Physiol Rev, 2003, 83 (3): 835-70
[122] Hebda, P.A. Stimulatory effects of transforming growth factor-beta and epidermal growth factor on epidermal cell outgrowth from porcine skin explant cultures. J Invest Dermatol, 1988, 91 (5): 440-5
[123] Sellheyer, K., Bickenbach, J.R., Rothnagel, J.A. et al. Inhibition of skin development by overexpression of transforming growth factor beta 1 in the epidermis of transgenic mice. Proc Natl Acad Sci U S A, 1993, 90 (11): 5237-41
[124] Yang, L., Mao, C., Teng, Y. et al. Targeted disruption of Smad4 in mouse epidermis results in failure of hair follicle cycling and formation of skin tumors. Cancer Res, 2005, 65 (19): 8671-8
[125] Ashcroft, G.S., Yang, X., Glick, A.B. et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol, 1999, 1 (5): 260-6
[126] Chan, T., Ghahary, A., Demare, J. et al. Development, characterization, and wound healing of the keratin 14 promoted transforming growth factor-beta1 transgenic mouse. Wound Repair Regen, 2002, 10 (3): 177-87
[127] Yang, L., Chan, T., Demare, J. et al. Healing of burn wounds in transgenic mice overexpressing transforming growth factor-beta 1 in the epidermis. Am J Pathol, 2001, 159 (6): 2147-57
[128] Gloy, J., Hikasa, H. and Sokol, S.Y. Frodo interacts with Dishevelled to transduce Wnt signals. Nat Cell Biol, 2002, 4 (5): 351-7
[129] Katoh, M. and Katoh, M. Identification and characterization of human DAPPER1 and DAPPER2 genes in silico. Int J Oncol, 2003, 22 (4): 907-13
[130] Katoh, M. and Katoh, M. Identification and characterization of rat Dact1 and Dact2 genes in silico. Int J Mol Med, 2005, 15 (6): 1045-9
[131] Zhang, L., Gao, X., Wen, J. et al. Dapper 1 antagonizes Wnt signaling by promoting dishevelled degradation. J Biol Chem, 2006, 281 (13): 8607-12
[132] Yau, T.O., Chan, C.Y., Chan, K.L. et al. HDPR1, a novel inhibitor of the WNT/beta-catenin signaling, is frequently downregulated in hepatocellular carcinoma: involvement of methylation-mediated gene silencing. Oncogene, 2005, 24 (9): 1607-14
[133] Waxman, J.S., Hocking, A.M., Stoick, C.L. et al. Zebrafish Dapper1 and Dapper2 play distinct roles in Wnt-mediated developmental processes. Development, 2004, 131 (23): 5909-21
[134] Fisher, D.A., Kivimae, S., Hoshino, J. et al. Three Dact gene family members are expressed during embryonic development and in the adult brains of mice. Dev Dyn, 2006, 235 (9): 2620-30
[135] Wong, H.C., Bourdelas, A., Krauss, A. et al. Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled. Mol Cell, 2003, 12 (5): 1251-60
[136] Brott, B.K. and Sokol, S.Y. A vertebrate homolog of the cell cycle regulator Dbf4 is an inhibitor of Wnt signaling required for heart development. Dev Cell, 2005, 8 (5): 703-15
[137] Su, Y., Zhang, L., Gao, X. et al. The evolutionally conserved activity of Dapper2 in antagonizing TGF-beta signaling. FASEB J, 2007, 21 (3): 682-90
[138] Brott, B.K. and Sokol, S.Y. Frodo proteins: modulators of Wnt signaling in vertebrate development. Differentiation, 2005, 73 (7): 323-9
[139] Gillhouse, M., Wagner Nyholm, M., Hikasa, H. et al. Two Frodo/Dapper homologs are expressed in the developing brain and mesoderm of zebrafish. Dev Dyn, 2004, 230 (3): 403-9
[140] Deng, C.X., Wynshaw-Boris, A., Shen, M.M. et al. Murine FGFR-1 is required for early postimplantation growth and axial organization. Genes Dev, 1994, 8 (24): 3045-57
[141] Sage, J., Mulligan, G.J., Attardi, L.D. et al. Targeted disruption of the three Rb-related genes leads to loss of G(1) control and immortalization. Genes Dev, 2000, 14 (23): 3037-50
[142] Stepp, M.A., Liu, Y., Pal-Ghosh, S. et al. Reduced migration, altered matrix and enhanced TGFbeta1 signaling are signatures of mouse keratinocytes lacking Sdc1. J Cell Sci, 2007, 120 (Pt 16): 2851-63
[143] Brody, D.L. and Holtzman, D.M. Morris water maze search strategy analysis in PDAPP mice before and after experimental traumatic brain injury. Exp Neurol, 2006, 197 (2): 330-40
[144] Huang, F.L., Huang, K.P., Wu, J. et al. Environmental enrichment enhances neurogranin expression and hippocampal learning and memory but fails to rescue the impairments of neurogranin null mutant mice. J Neurosci, 2006, 26 (23): 6230-7
[145] Teixeira, C.M., Pomedli, S.R., Maei, H.R. et al. Involvement of the anterior cingulate cortex in the expression of remote spatial memory. J Neurosci, 2006, 26 (29): 7555-64
[146] Zhang, C., Meng, F., Wang, C. et al. Identification of a novel alternative splicing form of human netrin-4 and analyzing the expression patterns in adult rat brain. Brain Res Mol Brain Res, 2004, 130 (1-2): 68-80
[147] Vassar, R., Rosenberg, M., Ross, S. et al. Tissue-specific and differentiation-specific expression of a human K14 keratin gene in transgenic mice. Proc Natl Acad Sci U S A, 1989, 86 (5): 1563-7
[148] Gat, U., DasGupta, R., Degenstein, L. et al. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell, 1998, 95 (5): 605-14
[149] Li, T., Inoue, A., Lahti, J.M. et al. Failure to proliferate and mitotic arrest of CDK11(p110/p58)-null mutant mice at the blastocyst stage of embryonic cell development. Mol Cell Biol, 2004, 24 (8): 3188-97
[150] Van Eynde, A., Nuytten, M., Dewerchin, M. et al. The nuclear scaffold protein NIPP1 is essential for early embryonic development and cell proliferation. Mol Cell Biol, 2004, 24 (13): 5863-74
[151] Luskin, M.B. Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron, 1993, 11 (1): 173-89
[152] Alvarez-Buylla, A. and Garcia-Verdugo, J.M. Neurogenesis in adult subventricular zone. J Neurosci, 2002, 22 (3): 629-34
[153] Taupin, P. Neural progenitor and stem cells in the adult central nervous system. Ann Acad Med Singapore, 2006, 35 (11): 814-20
[154] Barrow, J.R. Wnt/PCP signaling: a veritable polar star in establishing patterns of polarity in embryonic tissues. Semin Cell Dev Biol, 2006, 17 (2): 185-93
[155] Laping, N.J., Grygielko, E., Mathur, A. et al. Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542. Mol Pharmacol, 2002, 62 (1): 58-64
[156] Steffensen, B., Hakkinen, L. and Larjava, H. Proteolytic events of wound-healing--coordinated interactions among matrix metalloproteinases (MMPs), integrins, and extracellular matrix molecules. Crit Rev Oral Biol Med, 2001, 12 (5): 373-98
[157] Juhasz, I., Murphy, G.F., Yan, H.C. et al. Regulation of extracellular matrix proteins and integrin cell substratum adhesion receptors on epithelium during cutaneous human wound healing in vivo. Am J Pathol, 1993, 143 (5): 1458-69
[158] Zambruno, G., Marchisio, P.C., Marconi, A. et al. Transforming growth factor-beta 1 modulates beta 1 and beta 5 integrin receptors and induces the de novo expression of the alpha v beta 6 heterodimer in normal human keratinocytes: implications for wound healing. J Cell Biol, 1995, 129 (3): 853-65
[159] Martin, P. Wound healing--aiming for perfect skin regeneration. Science, 1997, 276 (5309): 75-81
[160] Grose, R., Hutter, C., Bloch, W. et al. A crucial role of beta 1 integrins for keratinocyte migration in vitro and during cutaneous wound repair. Development, 2002, 129 (9): 2303-15
[161] Gailit, J., Welch, M.P. and Clark, R.A. TGF-beta 1 stimulates expression of keratinocyte integrins during re-epithelialization of cutaneous wounds. J Invest Dermatol, 1994, 103 (2): 221-7
[162] Garlick, J.A. and Taichman, L.B. Fate of human keratinocytes during reepithelialization in an organotypic culture model. Lab Invest, 1994, 70 (6): 916-24
[163] Larjava, H., Salo, T., Haapasalmi, K. et al. Expression of integrins and basement membrane components by wound keratinocytes. J Clin Invest, 1993, 92 (3): 1425-35
[164] Hynes, R.O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell, 1992, 69 (1): 11-25
[165] Weinacker, A., Chen, A., Agrez, M. et al. Role of the integrin alpha v beta 6 in cell attachment to fibronectin. Heterologous expression of intact and secreted forms of the receptor. J Biol Chem, 1994, 269 (9): 6940-8
[166] Huang, X., Wu, J., Spong, S. et al. The integrin alphavbeta6 is critical for keratinocyte migration on both its known ligand, fibronectin, and on vitronectin. J Cell Sci, 1998, 111 ( Pt 15): 2189-95
[167] Thomas, G.J., Poomsawat, S., Lewis, M.P. et al. alpha v beta 6 Integrin upregulates matrix metalloproteinase 9 and promotes migration of normal oral keratinocytes. J Invest Dermatol, 2001, 116 (6): 898-904