Ror2 Enhances Polarity and Directional Migration of Primordial Germ Cells
The trafficking of primordial germ cells (PGCs) across multiple embryonic structures to the nascent gonads ensures the transmission of genetic information to the next generation through the gametes, yet our understanding of the mechanisms underlying PGC migration remains incomplete. Here we identify a role for the receptor tyrosine kinase-like protein Ror2 in PGC development. In a Ror2 mouse mutant we isolated in a genetic screen, PGC migration and survival are dysregulated, resulting in a diminished number of PGCs in the embryonic gonad. A similar phenotype in Wnt5a mutants suggests that Wnt5a acts as a ligand to Ror2 in PGCs, although we do not find evidence that WNT5A functions as a PGC chemoattractant. We show that cultured PGCs undergo polarization, elongation, and reorientation in response to the chemotactic factor SCF (secreted KitL), whereas Ror2 PGCs are deficient in these SCF-induced responses. In the embryo, migratory PGCs exhibit a similar elongated geometry, whereas their counterparts in Ror2 mutants are round. The protein distribution of ROR2 within PGCs is asymmetric, both in vitro and in vivo; however, this asymmetry is lost in Ror2 mutants. Together these results indicate that Ror2 acts autonomously to permit the polarized response of PGCs to KitL. We propose a model by which Wnt5a potentiates PGC chemotaxis toward secreted KitL by redistribution of Ror2 within the cell.
Vyšlo v časopise:
Ror2 Enhances Polarity and Directional Migration of Primordial Germ Cells. PLoS Genet 7(12): e32767. doi:10.1371/journal.pgen.1002428
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002428
Souhrn
The trafficking of primordial germ cells (PGCs) across multiple embryonic structures to the nascent gonads ensures the transmission of genetic information to the next generation through the gametes, yet our understanding of the mechanisms underlying PGC migration remains incomplete. Here we identify a role for the receptor tyrosine kinase-like protein Ror2 in PGC development. In a Ror2 mouse mutant we isolated in a genetic screen, PGC migration and survival are dysregulated, resulting in a diminished number of PGCs in the embryonic gonad. A similar phenotype in Wnt5a mutants suggests that Wnt5a acts as a ligand to Ror2 in PGCs, although we do not find evidence that WNT5A functions as a PGC chemoattractant. We show that cultured PGCs undergo polarization, elongation, and reorientation in response to the chemotactic factor SCF (secreted KitL), whereas Ror2 PGCs are deficient in these SCF-induced responses. In the embryo, migratory PGCs exhibit a similar elongated geometry, whereas their counterparts in Ror2 mutants are round. The protein distribution of ROR2 within PGCs is asymmetric, both in vitro and in vivo; however, this asymmetry is lost in Ror2 mutants. Together these results indicate that Ror2 acts autonomously to permit the polarized response of PGCs to KitL. We propose a model by which Wnt5a potentiates PGC chemotaxis toward secreted KitL by redistribution of Ror2 within the cell.
Zdroje
1. McLarenA 2003 Primordial germ cells in the mouse. Dev Biol 262 1 15
2. RunyanCSchaibleKMolyneauxKWangZLevinL 2006 Steel factor controls midline cell death of primordial germ cells and is essential for their normal proliferation and migration. Development 133 4861 4869
3. StevensLC 1967 Origin of testicular teratomas from primordial germ cells in mice. J Natl Cancer Inst 38 549 552
4. StevensLC 1984 Germ cell origin of testicular and ovarian teratomas. Transplant Proc 16 502 504
5. GreenJLKuntzSGSternbergPW 2008 Ror receptor tyrosine kinases: orphans no more. Trends Cell Biol 18 536 544
6. DeChiaraTMKimbleRBPoueymirouWTRojasJMasiakowskiP 2000 Ror2, encoding a receptor-like tyrosine kinase, is required for cartilage and growth plate development. Nat Genet 24 271 274
7. ForresterWCDellMPerensEGarrigaG 1999 A C. elegans Ror receptor tyrosine kinase regulates cell motility and asymmetric cell division. Nature 400 881 885
8. TakeuchiSTakedaKOishiINomiMIkeyaM 2000 Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation. Genes Cells 5 71 78
9. YamadaMUdagawaJMatsumotoAHashimotoRHattaT 2010 Ror2 is required for midgut elongation during mouse development. Dev Dyn 239 941 953
10. AndersonRFasslerRGeorges-LabouesseEHynesROBaderBL 1999 Mouse primordial germ cells lacking beta1 integrins enter the germline but fail to migrate normally to the gonads. Development 126 1655 1664
11. SchambonyAWedlichD 2007 Wnt-5A/Ror2 regulate expression of XPAPC through an alternative noncanonical signaling pathway. Dev Cell 12 779 792
12. YamamotoSNishimuraOMisakiKNishitaMMinamiY 2008 Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex. Dev Cell 15 23 36
13. HikasaHShibataMHirataniITairaM 2002 The Xenopus receptor tyrosine kinase Xror2 modulates morphogenetic movements of the axial mesoderm and neuroectoderm via Wnt signaling. Development 129 5227 5239
14. GreenJLInoueTSternbergPW 2008 Opposing Wnt pathways orient cell polarity during organogenesis. Cell 134 646 656
15. HeFXiongWYuXEspinoza-LewisRLiuC 2008 Wnt5a regulates directional cell migration and cell proliferation via Ror2-mediated noncanonical pathway in mammalian palate development. Development 135 3871 3879
16. NishitaMYooSKNomachiAKaniSSougawaN 2006 Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration. J Cell Biol 175 555 562
17. OishiISuzukiHOnishiNTakadaRKaniS 2003 The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells 8 645 654
18. NomachiANishitaMInabaDEnomotoMHamasakiM 2008 Receptor tyrosine kinase Ror2 mediates Wnt5a-induced polarized cell migration by activating c-Jun N-terminal kinase via actin-binding protein filamin A. J Biol Chem 283 27973 27981
19. YamaguchiTPBradleyAMcMahonAPJonesS 1999 A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development 126 1211 1223
20. MatsudaTNomiMIkeyaMKaniSOishiI 2001 Expression of the receptor tyrosine kinase genes, Ror1 and Ror2, during mouse development. Mech Dev 105 153 156
21. OishiITakeuchiSHashimotoRNagabukuroAUedaT 1999 Spatio-temporally regulated expression of receptor tyrosine kinases, mRor1, mRor2, during mouse development: implications in development and function of the nervous system. Genes Cells 4 41 56
22. GrosJHuJKVinegoniCFeruglioPFWeisslederR 2010 WNT5A/JNK and FGF/MAPK pathways regulate the cellular events shaping the vertebrate limb bud. Curr Biol 20 1993 2002
23. TakeuchiMNakabayashiJSakaguchiTYamamotoTSTakahashiH 2003 The prickle-related gene in vertebrates is essential for gastrulation cell movements. Curr Biol 13 674 679
24. ChoiSCSokolSY 2009 The involvement of lethal giant larvae and Wnt signaling in bottle cell formation in Xenopus embryos. Dev Biol 336 68 75
25. WeeraratnaATJiangYHostetterGRosenblattKDurayP 2002 Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell 1 279 288
26. WitzeESLitmanESArgastGMMoonRTAhnNG 2008 Wnt5a control of cell polarity and directional movement by polarized redistribution of adhesion receptors. Science 320 365 369
27. NarimatsuMBoseRPyeMZhangLMillerB 2009 Regulation of planar cell polarity by Smurf ubiquitin ligases. Cell 137 295 307
28. ShiWPeyrotSMMunroELevineM 2009 FGF3 in the floor plate directs notochord convergent extension in the Ciona tadpole. Development 136 23 28
29. HoffmannMSegbertCHelbigGBossingerO 2010 Intestinal tube formation in Caenorhabditis elegans requires vang-1 and egl-15 signaling. Dev Biol 339 268 279
30. Garcia-GarciaMJEggenschwilerJTCasparyTAlcornHLWylerMR 2005 Analysis of mouse embryonic patterning and morphogenesis by forward genetics. Proc Natl Acad Sci U S A 102 5913 5919
31. ChenYBellamyWPSeabraMCFieldMCAliBR 2005 ER-associated protein degradation is a common mechanism underpinning numerous monogenic diseases including Robinow syndrome. Hum Mol Genet 14 2559 2569
32. YeomYIFuhrmannGOvittCEBrehmAOhboK 1996 Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells. Development 122 881 894
33. YamadaMUdagawaJMatsumotoAHashimotoRHattaT 2010 Ror2 is required for midgut elongation during mouse development. Dev Dyn 239 941 953
34. Al-ShawiRAshtonSVUnderwoodCSimonsJP 2001 Expression of the Ror1 and Ror2 receptor tyrosine kinase genes during mouse development. Dev Genes Evol 211 161 171
35. MiseNFuchikamiTSugimotoMKobayakawaSIkeF 2008 Differences and similarities in the developmental status of embryo-derived stem cells and primordial germ cells revealed by global expression profiling. Genes Cells 13 863 877
36. MaraniEvan OersJWTetterooPAPoelmannREvan der VeekenJ 1986 Stage specific embryonic carbohydrate surface antigens of primordial germ cells in mouse embryos: FAL (S.S.E.A.-1) and globoside (S.S.E.A.-3). Acta Morphol Neerl Scand 24 103 110
37. DamjanovIFoxNKnowlesBBSolterDLangePH 1982 Immunohistochemical localization of murine stage-specific embryonic antigens in human testicular germ cell tumors. Am J Pathol 108 225 230
38. WangDEndersGC 1996 Expression of a specific mouse germ cell nuclear antigen (GCNA1) by early embryonic testicular teratoma cells in 129/Sv-Sl/+ mice. Cancer Lett 100 31 36
39. TamPPSnowMH 1981 Proliferation and migration of primordial germ cells during compensatory growth in mouse embryos. J Embryol Exp Morphol 64 133 147
40. MikelsAJNusseR 2006 Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS Biol 4 e115 doi:10.1371/journal.pbio.0040115
41. GuYRunyanCShoemakerASuraniAWylieC 2009 Steel factor controls primordial germ cell survival and motility from the time of their specification in the allantois, and provides a continuous niche throughout their migration. Development 136 1295 1303
42. AraTNakamuraYEgawaTSugiyamaTAbeK 2003 Impaired colonization of the gonads by primordial germ cells in mice lacking a chemokine, stromal cell-derived factor-1 (SDF-1). Proc Natl Acad Sci U S A 100 5319 5323
43. MolyneauxKAZinsznerHKunwarPSSchaibleKSteblerJ 2003 The chemokine SDF1/CXCL12 and its receptor CXCR4 regulate mouse germ cell migration and survival. Development 130 4279 4286
44. HaraKKanai-AzumaMUemuraMShitaraHTayaC 2009 Evidence for crucial role of hindgut expansion in directing proper migration of primordial germ cells in mouse early embryogenesis. Dev Biol 330 427 439
45. MikelsAMinamiYNusseR 2009 Ror2 receptor requires tyrosine kinase activity to mediate Wnt5A signaling. J Biol Chem 284 30167 30176
46. FariniDLa SalaGTedescoMDe FeliciM 2007 Chemoattractant action and molecular signaling pathways of Kit ligand on mouse primordial germ cells. Dev Biol 306 572 583
47. PetrieRJDoyleADYamadaKM 2009 Random versus directionally persistent cell migration. Nat Rev Mol Cell Biol 10 538 549
48. SutterlinCColanziA 2010 The Golgi and the centrosome: building a functional partnership. J Cell Biol 188 621 628
49. SchlessingerKMcManusEJHallA 2007 Cdc42 and noncanonical Wnt signal transduction pathways cooperate to promote cell polarity. J Cell Biol 178 355 361
50. AndersonRCopelandTKScholerHHeasmanJWylieC 2000 The onset of germ cell migration in the mouse embryo. Mech Dev 91 61 68
51. RunyanCGuYShoemakerALooijengaLWylieC 2008 The distribution and behavior of extragonadal primordial germ cells in Bax mutant mice suggest a novel origin for sacrococcygeal germ cell tumors. Int J Dev Biol 52 333 344
52. LairdDJvon AndrianUHWagersAJ 2008 Stem cell trafficking in tissue development, growth, and disease. Cell 132 612 630
53. ChawengsaksophakKSvingenTNgETEppTSpillerCM 2011 Loss of Wnt5a Disrupts Primordial Germ Cell Migration and Male Sexual Development in Mice. Biol Reprod
54. DolciSWilliamsDEErnstMKResnickJLBrannanCI 1991 Requirement for mast cell growth factor for primordial germ cell survival in culture. Nature 352 809 811
55. GodinIWylieCHeasmanJ 1990 Genital ridges exert long-range effects on mouse primordial germ cell numbers and direction of migration in culture. Development 108 357 363
56. McCoshenJAMcCallionDJ 1975 A study of the primordial germ cells during their migratory phase in Steel mutant mice. Experientia 31 589 590
57. GuYRunyanCShoemakerASuraniMAWylieC 2011 Membrane-bound steel factor maintains a high local concentration for mouse primordial germ cell motility, and defines the region of their migration. PLoS ONE 6 e25984 doi:10.1371/journal.pone.0025984
58. Mahakali ZamaAHudsonFP3rdBedellMA 2005 Analysis of hypomorphic KitlSl mutants suggests different requirements for KITL in proliferation and migration of mouse primordial germ cells. Biol Reprod 73 639 647
59. Blume-JensenPClaesson-WelshLSiegbahnAZseboKMWestermarkB 1991 Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis. Embo J 10 4121 4128
60. MeiningerCJYanoHRottapelRBernsteinAZseboKM 1992 The c-kit receptor ligand functions as a mast cell chemoattractant. Blood 79 958 963
61. NobesCDHallA 1999 Rho GTPases control polarity, protrusion, and adhesion during cell movement. J Cell Biol 144 1235 1244
62. PaganoniSFerreiraA 2003 Expression and subcellular localization of Ror tyrosine kinase receptors are developmentally regulated in cultured hippocampal neurons. J Neurosci Res 73 429 440
63. LevSYardenYGivolD 1992 Dimerization and activation of the kit receptor by monovalent and bivalent binding of the stem cell factor. J Biol Chem 267 15970 15977
64. SatoAYamamotoHSakaneHKoyamaHKikuchiA 2009 Wnt5a regulates distinct signalling pathways by binding to Frizzled2. EMBO J 29 41 54
65. LarueLDoughertyNPorterSMintzB 1992 Spontaneous malignant transformation of melanocytes explanted from Wf/Wf mice with a Kit kinase-domain mutation. Proc Natl Acad Sci U S A 89 7816 7820
66. HirotaS 2001 Gastrointestinal stromal tumors: their origin and cause. Int J Clin Oncol 6 1 5
67. SzaboPEHubnerKScholerHMannJR 2002 Allele-specific expression of imprinted genes in mouse migratory primordial germ cells. Mech Dev 115 157 160
68. PapaioannouVBehringerR 2005 Mouse Phenotypes: A Handbook of Mutation Analysis Cold Spring Harbor Cold Spring Harbor Laboratory Press
69. TakeuchiYMolyneauxKRunyanCSchaibleKWylieC 2005 The roles of FGF signaling in germ cell migration in the mouse. Development 132 5399 5409
70. GinsburgMSnowMHMcLarenA 1990 Primordial germ cells in the mouse embryo during gastrulation. Development 110 521 528
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 12
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
Najčítanejšie v tomto čísle
- Targeted Proteolysis of Plectin Isoform 1a Accounts for Hemidesmosome Dysfunction in Mice Mimicking the Dominant Skin Blistering Disease EBS-Ogna
- An Assessment of the Individual and Collective Effects of Variants on Height Using Twins and a Developmentally Informative Study Design
- Genomes Reveal Transition of Bacteria from Aquatic to Terrestrial Environments
- A Complex Genomic Rearrangement Involving the Locus Causes Dermal Hyperpigmentation in the Chicken