title: Conditional deletion of Msx homeobox genes in the uterus inhibits blastocyst implantation by altering uterine receptivity.
abstract: An effective bidirectional communication between an implantation-competent blastocyst and the receptive uterus is a prerequisite for mammalian reproduction. The blastocyst will implant only when this molecular cross-talk is established. Here we show that the muscle segment homeobox gene (Msh) family members Msx1 and Msx2, which are two highly conserved genes critical for epithelial-mesenchymal interactions during development, also play crucial roles in embryo implantation. Loss of Msx1/Msx2 expression correlates with altered uterine luminal epithelial cell polarity and affects E-cadherin/β-catenin complex formation through the control of Wnt5a expression. Application of Wnt5a in vitro compromised blastocyst invasion and trophoblast outgrowth on cultured uterine epithelial cells. The finding that Msx1/Msx2 genes are critical for conferring uterine receptivity and readiness to implantation could have clinical significance, because compromised uterine receptivity is a major cause of pregnancy failure in IVF programs.
authors.affiliation: Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: Takiko
authors.initials: T
authors.lastname: Daikoku
authors.forename: Jeeyeon
authors.initials: J
authors.lastname: Cha
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Sun
authors.forename: Susanne
authors.initials: S
authors.lastname: Tranguch
authors.forename: Huirong
authors.initials: H
authors.lastname: Xie
authors.forename: Tomoko
authors.initials: T
authors.lastname: Fujita
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hirota
authors.forename: John
authors.initials: J
authors.lastname: Lydon
authors.forename: Francesco
authors.initials: F
authors.lastname: DeMayo
authors.forename: Robert
authors.initials: R
authors.lastname: Maxson
authors.forename: Sudhansu K
authors.initials: SK
authors.lastname: Dey
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000235:genetics / Q000502:physiology; D010064:Embryo Implantation / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005298:Fertility / Q000235:genetics / Q000502:physiology; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics; D051957:MSX1 Transcription Factor / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011247:Pregnancy; D011256:Pregnancy Outcome; D014599:Uterus / Q000166:cytology / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D018398:Homeodomain Proteins; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D051957:MSX1 Transcription Factor; C084119:MSX2 protein; C484084:Msx1 protein, mouse; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D051176:beta Catenin
references.citation: Development. 1994 Feb;120(2):335-45
references.pmid: 7908629
references.citation: Trends Genet. 1995 Oct;11(10):405-11
references.pmid: 7482767
references.citation: Int J Dev Biol. 1996 Feb;40(1):389-93
references.pmid: 8735953
references.citation: J Reprod Fertil. 1981 Jan;61(1):235-40
references.pmid: 7452622
references.citation: Dev Cell. 2003 Sep;5(3):367-77
references.pmid: 12967557
references.citation: Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10159-62
references.pmid: 8234270
references.citation: Mol Cell Biol. 2002 Feb;22(4):1172-83
references.pmid: 11809808
references.citation: Genes Dev. 2010 Nov 15;24(22):2517-30
references.pmid: 21078818
references.citation: Nat Rev Genet. 2007 Feb;8(2):126-38
references.pmid: 17230199
references.citation: Development. 2003 Sep;130(17):4025-36
references.pmid: 12874124
references.citation: Genesis. 2005 Feb;41(2):58-66
references.pmid: 15682389
references.citation: Science. 1994 Dec 2;266(5190):1508-18
references.pmid: 7985020
references.citation: Mol Endocrinol. 2005 Mar;19(3):683-97
references.pmid: 15528267
references.citation: J Cell Biol. 1985 Dec;101(6):2085-94
references.pmid: 2415535
references.citation: Development. 2008 Nov;135(22):3719-29
references.pmid: 18927149
references.citation: Cell. 1997 Oct 17;91(2):197-208
references.pmid: 9346237
references.citation: Biochem Biophys Res Commun. 1996 Oct 3;227(1):257-65
references.pmid: 8858134
references.citation: Endocr Rev. 2004 Jun;25(3):341-73
references.pmid: 15180948
references.citation: Nature. 1992 Sep 3;359(6390):76-9
references.pmid: 1522892
references.citation: Hum Reprod. 2005 Aug;20(8):2104-17
references.pmid: 15878921
references.citation: Biol Proced Online. 2006;8:69-76
references.pmid: 17033697
references.citation: Mol Endocrinol. 2004 Dec;18(12):3035-49
references.pmid: 15358837
references.citation: Biochem J. 2001 Jan 1;353(Pt 1):13-22
references.pmid: 11115394
references.citation: Development. 1998 Nov;125(21):4325-33
references.pmid: 9753686
references.citation: Development. 1994 May;120(5):1071-83
references.pmid: 8026321
references.citation: Mol Endocrinol. 2001 Nov;15(11):1983-92
references.pmid: 11682628
references.citation: Biochemistry. 1997 Aug 26;36(34):10451-62
references.pmid: 9265625
references.citation: J Clin Invest. 2010 Mar;120(3):803-15
references.pmid: 20124728
references.citation: Development. 1999 Mar;126(6):1211-23
references.pmid: 10021340
references.citation: J Biol Chem. 2003 Aug 1;278(31):29057-64
references.pmid: 12754255
references.citation: Endocrinology. 2002 Jun;143(6):2119-38
references.pmid: 12021176
references.citation: Dev Biol. 2002 May 15;245(2):280-90
references.pmid: 11977981
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1047-52
references.pmid: 11158592
references.citation: Cell Calcium. 2005 Sep-Oct;38(3-4):439-46
references.pmid: 16099039
references.citation: Nat Rev Genet. 2006 Mar;7(3):185-99
references.pmid: 16485018
references.citation: Development. 2002 May;129(10):2459-72
references.pmid: 11973277
references.citation: Oncogene. 2008 Nov 24;27(55):6920-9
references.pmid: 19029934
references.citation: Annu Rev Physiol. 2000;62:353-75
references.pmid: 10845095
references.citation: J Biol Chem. 1996 May 17;271(20):11971-8
references.pmid: 8662595
references.citation: J Endocrinol. 1968 Nov;42(3):453-63
references.pmid: 4179775
references.citation: J Biol Chem. 2004 Nov 26;279(48):50102-9
references.pmid: 15375164
references.citation: Prog Histochem Cytochem. 1993;27(3):1-66
references.pmid: 8265798
references.citation: Nature. 2005 May 5;435(7038):104-8
references.pmid: 15875025
references.citation: Sci Signal. 2008 Sep 02;1(35):re9
references.pmid: 18765832
references.citation: Reproduction. 2004 Dec;128(6):669-78
references.pmid: 15579584
references.citation: Dev Biol. 1999 Apr 15;208(2):488-501
references.pmid: 10191061
references.citation: J Cell Biol. 1999 Jun 28;145(7):1497-509
references.pmid: 10385528
references.citation: Nat Genet. 1994 Apr;6(4):348-56
references.pmid: 7914451
references.citation: J Reprod Fertil. 1966 Dec;12(3):593-5
references.pmid: 5928277
references.citation: Dev Genet. 1997;21(1):6-20
references.pmid: 9291576
references.citation: Mol Hum Reprod. 2003 May;9(5):253-64
references.pmid: 12728018
references.citation: Development. 2002 Jun;129(12):2879-89
references.pmid: 12050136
references.citation: Mech Dev. 1996 Apr;55(2):185-99
references.pmid: 8861098
references.citation: Trends Cell Biol. 2008 Nov;18(11):536-44
references.pmid: 18848778
references.citation: Nature. 1993 May 27;363(6427):361-4
references.pmid: 8497320
references.citation: Biol Reprod. 1975 Feb;12(1):41-65
references.pmid: 1095088
references.citation: Mol Cell Biol. 2007 Aug;27(15):5468-78
references.pmid: 17515606
references.citation: Mech Dev. 1997 Jul;65(1-2):123-33
references.pmid: 9256350
references.citation: Development. 1996 Oct;122(10):3035-44
references.pmid: 8898217
references.citation: Genes Cells. 2003 Jul;8(7):645-54
references.pmid: 12839624
references.citation: BMC Evol Biol. 2009 Jan 20;9:18
references.pmid: 19154605
references.citation: J Biol Chem. 2009 Apr 17;284(16):10968-79
references.pmid: 19244247
references.citation: Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):1764-9
references.pmid: 8700832
references.citation: Mol Endocrinol. 2005 Mar;19(3):669-82
references.pmid: 15591538
references.citation: Biol Reprod. 2009 May;80(5):989-1000
references.pmid: 19164167
references.citation: Development. 2004 May;131(9):2061-72
references.pmid: 15073149
references.citation: Curr Opin Neurobiol. 2000 Feb;10(1):63-71
references.pmid: 10679430
references.citation: Nat Genet. 2000 Apr;24(4):391-5
references.pmid: 10742104
references.citation: Dev Dyn. 2010 Jan;239(1):1-15
references.pmid: 19530173
references.citation: Mol Endocrinol. 1999 Jun;13(6):1005-17
references.pmid: 10379898
references.citation: Cell. 1995 Aug 25;82(4):611-20
references.pmid: 7664340
references.citation: Science. 2008 Apr 18;320(5874):365-9
references.pmid: 18420933
references.citation: Hum Reprod. 1998 Nov;13(11):3211-9
references.pmid: 9853883
references.citation: Mol Endocrinol. 2000 Aug;14(8):1147-61
references.pmid: 10935540
references.citation: Nat Genet. 2006 Oct;38(10):1204-9
references.pmid: 16951680
references.citation: Mol Endocrinol. 2004 May;18(5):1238-50
references.pmid: 14976223
references.citation: J Exp Med. 1998 Nov 16;188(10):1955-65
references.pmid: 9815272
references.citation: Reproduction. 2006 Feb;131(2):341-9
references.pmid: 16452727
references.citation: Development. 2001 Jun;128(12):2373-84
references.pmid: 11493556
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8579-84
references.pmid: 15930138
references.citation: Genesis. 2007 Aug;45(8):477-81
references.pmid: 17654563
references.citation: J Cell Physiol. 1996 Oct;169(1):1-14
references.pmid: 8841417
references.citation: Cancer Res. 2008 Jul 15;68(14):5619-27
references.pmid: 18632614