Abstract
Wnt signaling has been demonstrated to have extensive roles during embryogenesis. The Wnt family is highly conserved. In mice, there are 19 Wnt genes. Dickkopf (Dkk), through its interactions with Wnt co-receptors, low-density lipoprotein receptor-related protein (LRP), Frizzled and Kremen, can act as a negative regulator to block the Wnt-signaling pathway. There are four Dkk genes in the human genome, and three in that of the mouse. Dkk1 is involved in a variety of craniofacial developmental processes and behaves as a strong head inducer and limb regulator. Dkk1 mutant mice are embryonic-lethal. Here, we investigated the effects of Dkk1 on the differentiation of murine ESCs in both the ESC and embryoid body (EB) states. The results demonstrate that Dkk1 overexpression can initiate the differentiation program of ESCs toward neuroectoderm. We believe this finding can augment our understanding of mouse ESC differentiation.
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References
Aubert J.; Dunstan H.; Chambers I.; Smith A. Functional gene screening in embryonic stem cells implicates Wnt antagonism in neural differentiation. Nat. Biotechnol 20: 1240–1245; 2002. doi:10.1038/nbt763.
Bafico A.; Liu G.; Yaniv A.; Gazit A.; Aaronson S. A. Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat. Cell. Biol 3: 683–686; 2001. doi:10.1038/35083081.
Barbacci E.; Reber M.; Ott M. O.; et al. Variant hepatocyte nuclear factor 1 is required for visceral endoderm specification. Development 126: 4795–4805; 1999.
Ben-Shushan E.; Sharir H.; Pikarsky E.; Bergman Y. A dynamic balance between ARP-1/COUP-TFII, EAR-3/COUP-TFI, and retinoic acid receptor:retinoid X receptor heterodimers regulates Oct-3/4 expression in embryonal carcinoma cells. Mol. Cell Biol 15: 1034–1048; 1995.
Camenisch G.; Gruber M.; Donoho G.; et al. A polyoma-based episomal vector efficiently expresses exogenous genes in mouse embryonic stem cells. Nucleic Acids Res 24: 3707–3713; 1996. doi:10.1093/nar/24.19.3707.
Chambers I.; Colby D.; Robertson M.; et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113: 643–655; 2003. doi:10.1016/S0092-8674(03)00392-1.
Coffinier C.; Thepot D.; Babinet C.; Yaniv M.; Barra J. Essential role for the homeoprotein vHNF1/HNF1beta in visceral endoderm differentiation. Development 126: 4785–4794; 1999.
Coucouvanis E.; Martin G.R. Signals for death and survival: a two-step mechanism for cavitation in the vertebrate embryo. Cell 83: 279–287; 1995. doi:10.1016/0092-8674(95)90169-8.
del Barco Barrantes I.; Davidson G.; Grone H. J.; Westphal H.; Niehrs C. Dkk1 and noggin cooperate in mammalian head induction. Genes Dev 17: 2239–2244; 2003. doi:10.1101/gad.269103.
Duncan S. A.; Nagy A.; Chan W. Murine gastrulation requires HNF-4 regulated gene expression in the visceral endoderm: tetraploid rescue of Hnf-4(−/−) embryos. Development 124: 279–287; 1997.
Duncan S. A.; Navas M. A.; Dufort D.; Rossant J.; Stoffel M. Regulation of a transcription factor network required for differentiation and metabolism. Science 281: 692–695; 1998. doi:10.1126/science.281.5377.692.
Fujikura J.; Yamato E.; Yonemura S.; et al. Differentiation of embryonic stem cells is induced by GATA factors. Genes Dev 16: 784–789; 2002. doi:10.1101/gad.968802.
Gassmann M.; Donoho G.; Berg P. Maintenance of an extrachromosomal plasmid vector in mouse embryonic stem cells. Proc Natl Acad Sci USA 92: 1292–1296; 1995. doi:10.1073/pnas.92.5.1292.
Glinka A.; Wu W.; Delius H.; et al. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature 391: 357–362; 1998. doi:10.1038/34848.
Gu G.; Wells J. M.; Dombkowski D.; et al. Global expression analysis of gene regulatory pathways during endocrine pancreatic development. Development 131: 165–179; 2004. doi:10.1242/dev.00921.
Haegele L.; Ingold B.; Naumann H.; et al. Wnt signalling inhibits neural differentiation of embryonic stem cells by controlling bone morphogenetic protein expression. Mol. Cell Neurosci 24: 696–708; 2003. doi:10.1016/S1044-7431(03)00232-X.
Hashimoto H.; Itoh M.; Yamanaka Y.; et al. Zebrafish Dkk1 functions in forebrain specification and axial mesendoderm formation. Dev. Biol 217: 138–152; 2000. doi:10.1006/dbio.1999.9537.
Jackson M.; Baird J. W.; Cambray N.; et al. Cloning and characterization of Ehox, a novel homeobox gene essential for embryonic stem cell differentiation. J. Biol. Chem 277: 38683–38692; 2002. doi:10.1074/jbc.M203459200.
Kuhnert F.; Davis C. R.; Wang H. T.; et al. Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc. Natl. Acad. Sci. USA 101: 266–271; 2004. doi:10.1073/pnas.2536800100.
Kuo C. T.; Morrisey E. E.; Anandappa R.; et al. GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev 11: 1048–1060; 1997. doi:10.1101/gad.11.8.1048.
Lake J.; Rathjen J.; Remiszewski J.; Rathjen P. D. Reversible programming of pluripotent cell differentiation. J. Cell Sci 113Pt 3: 555–566; 2000.
Mao B.; Wu W.; Li Y.; et al. LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature 411: 321–325; 2001. doi:10.1038/35077108.
Mason I. J.; Taylor A.; Williams J. G.; Sage H.; Hogan B. L. Evidence from molecular cloning that SPARC, a major product of mouse embryo parietal endoderm, is related to an endothelial cell ‘culture shock’ glycoprotein of Mr 43,000. Embo J 5: 1465–1472; 1986.
Mitsui K.; Tokuzawa Y.; Itoh H.; et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 113: 631–642; 2003. doi:10.1016/S0092-8674(03)00393-3.
Morrisey E. E.; Ip H. S.; Lu M. M.; Parmacek M. S. Parmacek, M. S. GATA-6: a zinc finger transcription factor that is expressed in multiple cell lineages derived from lateral mesoderm. Dev. Biol 177: 309–322; 1996. doi:10.1006/dbio.1996.0165.
Morrisey E. E.; Musco S.; Chen M. Y.; et al. The gene encoding the mitogen-responsive phosphoprotein Dab2 is differentially regulated by GATA-6 and GATA-4 in the visceral endoderm. J. Biol. Chem 275: 19949–19954; 2000. doi:10.1074/jbc.M001331200.
Mukhopadhyay M.; Shtrom S.; Rodriguez-Esteban C.; et al. Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Dev. Cell 1: 423–434; 2001. doi:10.1016/S1534-5807(01)00041-7.
Murray P.; Edgar D. Regulation of programmed cell death by basement membranes in embryonic development. J. Cell Biol 150: 1215–1221; 2000. doi:10.1083/jcb.150.5.1215.
Murray P.; Edgar D. The regulation of embryonic stem cell differentiation by leukaemia inhibitory factor (LIF). Differentiation 68: 227–234; 2001. doi:10.1046/j.1432-0436.2001.680410.x.
Murray P.; Edgar D. Regulation of laminin and COUP-TF expression in extraembryonic endodermal cells. Mech. Dev 101: 213–215; 2001. doi:10.1016/S0925-4773(00)00554-2.
Nie X. Dkk1-2, and -3 expression in mouse craniofacial development. J. Mol. Histol 36: 367–372; 2005. doi:10.1007/s10735-005-9008-3.
Niehrs C. Head in the WNT: the molecular nature of Spemann’s head organizer. Trends Genet 15: 314–319; 1999. doi:10.1016/S0168-9525(99)01767-9.
Niwa H.; Masui S.; Chambers I.; Smith A. G.; Miyazaki J. Phenotypic complementation establishes requirements for specific POU domain and generic transactivation function of Oct-3/4 in embryonic stem cells. Mol. Cell Biol 22: 1526–1536; 2002. doi:10.1128/MCB.22.5.1526-1536.2002.
Pearce J. J.; Penny G.; Rossant J. A mouse cerberus/Dan-related gene family. Dev. Biol 209: 98–110; 1999. doi:10.1006/dbio.1999.9240.
Polesskaya A.; Seale P.; Rudnicki M. A. Wnt signaling induces the myogenic specification of resident CD45+ adult stem cells during muscle regeneration. Cell 113: 841–852; 2003. doi:10.1016/S0092-8674(03)00437-9.
Rathjen J.; Dunn S.; Bettess M. D.; Rathjen P. D. Lineage specific differentiation of pluripotent cells in vitro: a role for extraembryonic cell types. Reprod. Fertil. Dev 13: 15–22; 2001. doi:10.1071/RD00079.
Sato N.; Meijer L.; Skaltsounis L.; Greengard P.; Brivanlou A. H. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat. Med 10: 55–63; 2004. doi:10.1038/nm979.
Semenov M. V.; Tamai K.; Brott B. K.; et al. Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr. Biol 11: 951–961; 2001. doi:10.1016/S0960-9822(01)00290-1.
Senior P. V.; Critchley D. R.; Beck F.; Walker R. A.; Varley J. M. The localization of laminin mRNA and protein in the postimplantation embryo and placenta of the mouse: an in situ hybridization and immunocytochemical study. Development 104: 431–446; 1988.
Shinya M.; Eschbach C.; Clark M.; Lehrach H.; Furutani-Seiki M.; et al. Zebrafish Dkk1, induced by the pre-MBT Wnt signaling, is secreted from the prechordal plate and patterns the anterior neural plate. Mech. Dev 98: 3–17; 2000. doi:10.1016/S0925-4773(00)00433-0.
Smith A. G. Culture and differentiation of embryonic stem cells. J. Tiss. Cult. Meth 13: 89–94; 1991. doi:10.1007/BF01666137.
Smyth N.; Vatansever H. S.; Murray P.; et al. Absence of basement membranes after targeting the LAMC1 gene results in embryonic lethality due to failure of endoderm differentiation. J. Cell Biol 144: 151–160; 1999. doi:10.1083/jcb.144.1.151.
Timpl R. Macromolecular organization of basement membranes. Curr. Opin. Cell. Biol 8: 618–624; 1996. doi:10.1016/S0955-0674(96)80102-5.
Vallier L.; Reynolds D.; Pedersen R. A. Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway. Dev. Biol 275: 403–421; 2004. doi:10.1016/j.ydbio.2004.08.031.
Verani R.; Cappuccio I.; Spinsanti P.; et al. Expression of the Wnt inhibitor Dickkopf-1 is required for the induction of neural markers in mouse embryonic stem cells differentiating in response to retinoic acid. J. Neurochem 100: 242–250; 2007. doi:10.1111/j.1471-4159.2006.04207.x.
Watanabe K.; Kamiya D.; Nishiyama A.; et al. Directed differentiation of telencephalic precursors from embryonic stem cells. Nat. Neurosci 8: 288–296; 2005. doi:10.1038/nn1402.
Wells J. M.; Melton D. A. Early mouse endoderm is patterned by soluble factors from adjacent germ layers. Development 127: 1563–1572; 2000.
Wilkinson D. G.; Bhatt S.; Herrmann B. G. Expression pattern of the mouse T gene and its role in mesoderm formation. Nature 343: 657–659; 1990. doi:10.1038/343657a0.
Wu W.; Glinka A.; Delius H.; Niehrs C. Mutual antagonism between dickkopf1 and dickkopf2 regulates Wnt/beta-catenin signalling. Curr. Biol 10: 1611–1614; 2000. doi:10.1016/S0960-9822(00)00868-X.
Yoshikawa Y.; Fujimori T.; McMahon A. P.; Takada S. Evidence that absence of Wnt-3a signaling promotes neuralization instead of paraxial mesoderm development in the mouse. Dev. Biol 183: 234–242; 1997. doi:10.1006/dbio.1997.8502.
Zakin L.; Reversade B.; Virlon B.; et al. Gene expression profiles in normal and Otx2−/− early gastrulating mouse embryos. Proc. Natl. Acad. Sci. USA 97: 14388–14393; 2000. doi:10.1073/pnas.011513398.
Zhang C.; Ye X.; Zhang H.; Ding M.; Deng H. GATA factors induce mouse embryonic stem cell differentiation toward extraembryonic endoderm. Stem Cells Dev 16: 605–614; 2007. doi:10.1089/scd.2006.0077.
Acknowledgments
We especially thank Austin Smith and Ian Chambers for providing the E14/T cells. Dkk1 DNA was kindly provided by Christof Niehrs (Division of Molecular Embryology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany) and Calvin J. Kuo (Department of Medicine, Stanford University School of Medicine, Center for Clinical Sciences Research 3100, 269 Campus Drive, Stanford, CA 94305, USA.). This work was supported by the Fund for Excellent Junior Scientist Award of Shandong Province to C. Zhang (2006BS02007), and the National Natural Science Foundation of China (Grant No. 30771737).
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Kong, X.B., Zhang, C. Dickkopf (Dkk) 1 promotes the differentiation of mouse embryonic stem cells toward neuroectoderm. In Vitro Cell.Dev.Biol.-Animal 45, 185–193 (2009). https://doi.org/10.1007/s11626-008-9157-2
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DOI: https://doi.org/10.1007/s11626-008-9157-2