Igf1r Signaling Is Indispensable for Preimplantation Development and Is Activated via a Novel Function of E-cadherin
Insulin-like growth factor I receptor (Igf1r) signaling controls proliferation, differentiation, growth, and cell survival in many tissues; and its deregulated activity is involved in tumorigenesis. Although important during fetal growth and postnatal life, a function for the Igf pathway during preimplantation development has not been described. We show that abrogating Igf1r signaling with specific inhibitors blocks trophectoderm formation and compromises embryo survival during murine blastocyst formation. In normal embryos total Igf1r is present throughout the membrane, whereas the activated form is found exclusively at cell contact sites, colocalizing with E-cadherin. Using genetic domain switching, we show a requirement for E-cadherin to maintain proper activation of Igf1r. Embryos expressing exclusively a cadherin chimera with N-cadherin extracellular and E-cadherin intracellular domains (NcEc) fail to form a trophectoderm and cells die by apoptosis. In contrast, homozygous mutant embryos expressing a reverse-structured chimera (EcNc) show trophectoderm survival and blastocoel cavitation, indicating a crucial and non-substitutable role of the E-cadherin ectodomain for these processes. Strikingly, blastocyst formation can be rescued in homozygous NcEc embryos by restoring Igf1r signaling, which enhances cell survival. Hence, perturbation of E-cadherin extracellular integrity, independent of its cell-adhesion function, blocked Igf1r signaling and induced cell death in the trophectoderm. Our results reveal an important and yet undiscovered function of Igf1r during preimplantation development mediated by a unique physical interaction between Igf1r and E-cadherin indispensable for proper receptor activation and anti-apoptotic signaling. We provide novel insights into how ligand-dependent Igf1r activity is additionally gated to sense developmental potential in utero and into a bifunctional role of adhesion molecules in contact formation and signaling.
Vyšlo v časopise:
Igf1r Signaling Is Indispensable for Preimplantation Development and Is Activated via a Novel Function of E-cadherin. PLoS Genet 8(3): e32767. doi:10.1371/journal.pgen.1002609
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002609
Souhrn
Insulin-like growth factor I receptor (Igf1r) signaling controls proliferation, differentiation, growth, and cell survival in many tissues; and its deregulated activity is involved in tumorigenesis. Although important during fetal growth and postnatal life, a function for the Igf pathway during preimplantation development has not been described. We show that abrogating Igf1r signaling with specific inhibitors blocks trophectoderm formation and compromises embryo survival during murine blastocyst formation. In normal embryos total Igf1r is present throughout the membrane, whereas the activated form is found exclusively at cell contact sites, colocalizing with E-cadherin. Using genetic domain switching, we show a requirement for E-cadherin to maintain proper activation of Igf1r. Embryos expressing exclusively a cadherin chimera with N-cadherin extracellular and E-cadherin intracellular domains (NcEc) fail to form a trophectoderm and cells die by apoptosis. In contrast, homozygous mutant embryos expressing a reverse-structured chimera (EcNc) show trophectoderm survival and blastocoel cavitation, indicating a crucial and non-substitutable role of the E-cadherin ectodomain for these processes. Strikingly, blastocyst formation can be rescued in homozygous NcEc embryos by restoring Igf1r signaling, which enhances cell survival. Hence, perturbation of E-cadherin extracellular integrity, independent of its cell-adhesion function, blocked Igf1r signaling and induced cell death in the trophectoderm. Our results reveal an important and yet undiscovered function of Igf1r during preimplantation development mediated by a unique physical interaction between Igf1r and E-cadherin indispensable for proper receptor activation and anti-apoptotic signaling. We provide novel insights into how ligand-dependent Igf1r activity is additionally gated to sense developmental potential in utero and into a bifunctional role of adhesion molecules in contact formation and signaling.
Zdroje
1. CockburnKRossantJ 2010 Making the blastocyst: lessons from the mouse. J Clin Invest 120 995 1003
2. RossantJTamPP 2009 Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse. Development 136 701 713
3. AvilionAANicolisSKPevnyLHPerezLVivianN 2003 Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 17 126 140
4. ChazaudCYamanakaYPawsonTRossantJ 2006 Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. Dev Cell 10 615 624
5. NicholsJZevnikBAnastassiadisKNiwaHKlewe-NebeniusD 1998 Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95 379 391
6. NishiokaNInoueKAdachiKKiyonariHOtaM 2009 The Hippo Signaling Pathway Components Lats and Yap Pattern Tead4 Activity to Distinguish Mouse Trophectoderm from Inner Cell Mass. Dev Cell 16 398 410
7. StrumpfDMaoCAYamanakaYRalstonAChawengsaksophakK 2005 Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst. Development 132 2093 2102
8. StemmlerMP 2008 Cadherins in development and cancer. Mol Biosyst 4 835 850
9. LarueLOhsugiMHirchenhainJKemlerR 1994 E-cadherin null mutant embryos fail to form a trophectoderm epithelium. Proc Natl Acad Sci U S A 91 8263 8267
10. RiethmacherDBrinkmannVBirchmeierC 1995 A targeted mutation in the mouse E-cadherin gene results in defective preimplantation development. Proc Natl Acad Sci U S A 92 855 859
11. De VriesWNEvsikovAVHaacBEFancherKSHolbrookAE 2004 Maternal beta-catenin and E-cadherin in mouse development. Development 131 4435 4445
12. StephensonROYamanakaYRossantJ 2010 Disorganized epithelial polarity and excess trophectoderm cell fate in preimplantation embryos lacking E-cadherin. Development 137 3383 3391
13. RadiceGLRayburnHMatsunamiHKnudsenKATakeichiM 1997 Developmental defects in mouse embryos lacking N-cadherin. Dev Biol 181 64 78
14. LuoYFerreira-CornwellMBaldwinHKostetskiiILenoxJ 2001 Rescuing the N-cadherin knockout by cardiac-specific expression of N- or E-cadherin. Development 128 459 469
15. AberleHButzSStappertJWeissigHKemlerR 1994 Assembly of the cadherin-catenin complex in vitro with recombinant proteins. J Cell Sci 107 Pt 12 3655 3663
16. ReynoldsABDanielJMcCreaPDWheelockMJWuJ 1994 Identification of a new catenin: the tyrosine kinase substrate p120cas associates with E-cadherin complexes. Mol Cell Biol 14 8333 8342
17. LiGSatyamoorthyKHerlynM 2001 N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res 61 3819 3825
18. VleminckxKVakaetLJrMareelMFiersWvan RoyF 1991 Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66 107 119
19. WheelockMJShintaniYMaedaMFukumotoYJohnsonKR 2008 Cadherin switching. J Cell Sci 121 727 735
20. NietoMA 2009 Epithelial-Mesenchymal Transitions in development and disease: old views and new perspectives. Int J Dev Biol 53 1541 1547
21. KanNGStemmlerMPJunghansDKanzlerBde VriesWN 2007 Gene replacement reveals a specific role for E-cadherin in the formation of a functional trophectoderm. Development 134 31 41
22. StemmlerMPBedzhovI 2010 A Cdh1HA knock-in allele rescues the Cdh1-/- phenotype but shows essential Cdh1 function during placentation. Dev Dyn 239 2330 2344
23. AllanGJFlintDJPatelK 2001 Insulin-like growth factor axis during embryonic development. Reproduction 122 31 39
24. NakaeJKidoYAcciliD 2001 Distinct and overlapping functions of insulin and IGF-I receptors. Endocr Rev 22 818 835
25. LiuJPBakerJPerkinsASRobertsonEJEfstratiadisA 1993 Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75 59 72
26. Powell-BraxtonLHollingsheadPWarburtonCDowdMPitts-MeekS 1993 IGF-I is required for normal embryonic growth in mice. Genes Dev 7 2609 2617
27. LinTCYenJMGongKBHsuTTChenLR 2003 IGF-1/IGFBP-1 increases blastocyst formation and total blastocyst cell number in mouse embryo culture and facilitates the establishment of a stem-cell line. BMC Cell Biol 4 14
28. RileyJKCarayannopoulosMOWymanAHChiMMoleyKH 2006 Phosphatidylinositol 3-kinase activity is critical for glucose metabolism and embryo survival in murine blastocysts. J Biol Chem 281 6010 6019
29. StemmlerMPHechtAKemlerR 2005 E-cadherin intron 2 contains cis-regulatory elements essential for gene expression. Development 132 965 976
30. HardyKSpanosS 2002 Growth factor expression and function in the human and mouse preimplantation embryo. J Endocrinol 172 221 236
31. PakrasiPLJainAK 2008 Cyclooxygenase-2-derived endogenous prostacyclin reduces apoptosis and enhances embryo viability in mouse. Prostaglandins Leukot Essent Fatty Acids 79 27 33
32. HuangJCWunWSGoldsbyJSWunICNoorhasanD 2007 Stimulation of embryo hatching and implantation by prostacyclin and peroxisome proliferator-activated receptor delta activation: implication in IVF. Hum Reprod 22 807 814
33. KimJSChaeJISongBSLeeKSChooYK 2010 Iloprost, a prostacyclin analogue, stimulates meiotic maturation and early embryonic development in pigs. Reprod Fertil Dev 22 437 447
34. Fedor-ChaikenMHeinPWStewartJCBrackenburyRKinchMS 2003 E-cadherin binding modulates EGF receptor activation. Cell Commun Adhes 10 105 118
35. SuyamaKShapiroIGuttmanMHazanRB 2002 A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. Cancer Cell 2 301 314
36. HoschuetzkyHAberleHKemlerR 1994 Beta-catenin mediates the interaction of the cadherin-catenin complex with epidermal growth factor receptor. J Cell Biol 127 1375 1380
37. ThreadgillDWDlugoszAAHansenLATennenbaumTLichtiU 1995 Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269 230 234
38. CanoniciASteelantWRigotVKhomitch-BaudABoutaghou-CheridH 2008 Insulin-like growth factor-I receptor, E-cadherin and alpha v integrin form a dynamic complex under the control of alpha-catenin. Int J Cancer 122 572 582
39. GuvakovaMASurmaczE 1997 Overexpressed IGF-I receptors reduce estrogen growth requirements, enhance survival, and promote E-cadherin-mediated cell-cell adhesion in human breast cancer cells. Exp Cell Res 231 149 162
40. PokuttaSHerrenknechtKKemlerREngelJ 1994 Conformational changes of the recombinant extracellular domain of E-cadherin upon calcium binding. Eur J Biochem 223 1019 1026
41. McElroyBPowellJCMcCarthyJV 2007 The insulin-like growth factor 1 (IGF-1) receptor is a substrate for gamma-secretase-mediated intramembrane proteolysis. Biochem Biophys Res Commun 358 1136 1141
42. PeceSGutkindJS 2000 Signaling from E-cadherins to the MAPK pathway by the recruitment and activation of epidermal growth factor receptors upon cell-cell contact formation. J Biol Chem 275 41227 41233
43. QianXKarpovaTSheppardAMMcNallyJLowyDR 2004 E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases. EMBO J 23 1739 1748
44. BelfioreAFrascaFPandiniGSciaccaLVigneriR 2009 Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 30 586 623
45. FengZLevineAJ 2010 The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. Trends Cell Biol 20 427 434
46. LouviAAcciliDEfstratiadisA 1997 Growth-promoting interaction of IGF-II with the insulin receptor during mouse embryonic development. Dev Biol 189 33 48
47. KaneMTMorganPMCoonanC 1997 Peptide growth factors and preimplantation development. Hum Reprod Update 3 137 157
48. GumbinerBM 2005 Regulation of cadherin-mediated adhesion in morphogenesis. Nature Reviews Molecular Cell Biology 6 622 634
49. LammGMChristoforiG 1998 Impairment of survival factor function potentiates chemotherapy-induced apoptosis in tumor cells. Cancer Res 58 801 807
50. NeuenschwanderSSchwartzAWoodTLRobertsCTJrHennighausenL 1996 Involution of the lactating mammary gland is inhibited by the IGF system in a transgenic mouse model. J Clin Invest 97 2225 2232
51. PetrikJPellJMAranyEMcDonaldTJDeanWL 1999 Overexpression of insulin-like growth factor-II in transgenic mice is associated with pancreatic islet cell hyperplasia. Endocrinology 140 2353 2363
52. IngeLJBarweSPD'AmbrosioJGopalJLuK 2011 Soluble E-cadherin promotes cell survival by activating epidermal growth factor receptor. Exp Cell Res 317 838 848
53. LeeseHJBartonAM 1984 Pyruvate and glucose uptake by mouse ova and preimplantation embryos. J Reprod Fertil 72 9 13
54. PantaleonMKayePL 1996 IGF-I and insulin regulate glucose transport in mouse blastocysts via IGF-I receptor. Molecular Reproduction and Development 44 71 76
55. BoussadiaOKutschSHierholzerADelmasVKemlerR 2002 E-cadherin is a survival factor for the lactating mouse mammary gland. Mech Dev 115 53 62
56. PontaHShermanLHerrlichPA 2003 CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4 33 45
57. LibusovaLStemmlerMPHierholzerASchwarzHKemlerR 2010 N-cadherin can structurally substitute for E-cadherin during intestinal development but leads to polyp formation. Development 137 2297 2305
58. SeidelBBraegSAdlerGWedlichDMenkeA 2004 E- and N-cadherin differ with respect to their associated p120ctn isoforms and their ability to suppress invasive growth in pancreatic cancer cells. Oncogene 23 5532 5542
59. LewandoskiMWassarmanKMMartinGR 1997 Zp3-cre, a transgenic mouse line for the activation or inactivation of loxP-flanked target genes specifically in the female germ line. Curr Biol 7 148 151
60. VestweberDKemlerR 1984 Rabbit antiserum against a purified surface glycoprotein decompacts mouse preimplantation embryos and reacts with specific adult tissues. Exp Cell Res 152 169 178
61. KemlerRBruletPSchnebelenMTGaillardJJacobF 1981 Reactivity of monoclonal antibodies against intermediate filament proteins during embryonic development. J Embryol Exp Morphol 64 45 60
62. MesserschmidtDMKemlerR 2010 Nanog is required for primitive endoderm formation through a non-cell autonomous mechanism. Dev Biol 344 129 137
63. TanakaSKunathTHadjantonakisAKNagyARossantJ 1998 Promotion of trophoblast stem cell proliferation by FGF4. Science 282 2072 2075
64. NiwaHToyookaTShimosatoDStrumpfDTakahashiK 2005 Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell 123 917 929
65. AleksicTChitnisMMPerestenkoOVGaoSThomasPH 2010 Type 1 insulin-like growth factor receptor translocates to the nucleus of human tumor cells. Cancer Res 70 6412 6419
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 3
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