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The Wnt Frizzled Receptor MOM-5 Regulates the UNC-5 Netrin Receptor through Small GTPase-Dependent Signaling to Determine the Polarity of Migrating Cells


Cells are exposed to a multitude of environmental cues that are often eliciting additive, overlapping, or even conflicting inputs. How the information from multiple extracellular cues is integrated within the cell to generate distinct patterning is largely unknown. Netrin and Wnt signaling pathways are critical to multiple developmental processes and play key roles in normal development, as well as in malignancies. The involvement of these two signaling pathways in establishing cellular polarity is key to their ability to determine organ shape and to regulate cell and axon migration. Here, we reveal a regulatory link between the Wnt Frizzled receptor, MOM-5, and the Netrin receptor UNC-5. We present evidence showing that MOM-5/Frizzled signals through small GTPases to negatively regulate the UNC-5 Netrin receptor. This regulatory link enables the integration of Netrin and Wnt signaling pathways and facilitates their orchestrated function in mediating polarity of cell migration.


Vyšlo v časopise: The Wnt Frizzled Receptor MOM-5 Regulates the UNC-5 Netrin Receptor through Small GTPase-Dependent Signaling to Determine the Polarity of Migrating Cells. PLoS Genet 11(8): e32767. doi:10.1371/journal.pgen.1005446
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005446

Souhrn

Cells are exposed to a multitude of environmental cues that are often eliciting additive, overlapping, or even conflicting inputs. How the information from multiple extracellular cues is integrated within the cell to generate distinct patterning is largely unknown. Netrin and Wnt signaling pathways are critical to multiple developmental processes and play key roles in normal development, as well as in malignancies. The involvement of these two signaling pathways in establishing cellular polarity is key to their ability to determine organ shape and to regulate cell and axon migration. Here, we reveal a regulatory link between the Wnt Frizzled receptor, MOM-5, and the Netrin receptor UNC-5. We present evidence showing that MOM-5/Frizzled signals through small GTPases to negatively regulate the UNC-5 Netrin receptor. This regulatory link enables the integration of Netrin and Wnt signaling pathways and facilitates their orchestrated function in mediating polarity of cell migration.


Zdroje

1. Wong M-C, Schwarzbauer JE (2012) Gonad morphogenesis and distal tip cell migration in the Caenorhabditis elegans hermaphrodite. Wiley Interdiscip Rev Dev Biol 1: 519–531. 23559979

2. Levy-Strumpf N, Culotti JG (2014) Netrins and Wnts Function Redundantly to Regulate Antero-Posterior and Dorso-Ventral Guidance in C. elegans. PLoS Genet 10: e1004381. doi: 10.1371/journal.pgen.1004381 24901837

3. Wadsworth WG, Bhatt H, Hedgecock EM (1996) Neuroglia and pioneer neurons express UNC-6 to provide global and local netrin cues for guiding migrations in C. elegans. Neuron 16: 35–46. 8562088

4. Su M, Merz DC, Killeen MT, Zhou Y, Zheng H, et al. (2000) Regulation of the UNC-5 netrin receptor initiates the first reorientation of migrating distal tip cells in Caenorhabditis elegans. Development 127: 585–594. 10631179

5. Cabello J, Neukomm LJ, Günesdogan U, Burkart K, Charette SJ, et al. (2010) The Wnt pathway controls cell death engulfment, spindle orientation, and migration through CED-10/Rac. PLoS Biol 8: e1000297. doi: 10.1371/journal.pbio.1000297 20126385

6. Lundquist E a, Reddien PW, Hartwieg E, Horvitz HR, Bargmann CI (2001) Three C. elegans Rac proteins and several alternative Rac regulators control axon guidance, cell migration and apoptotic cell phagocytosis. Development 128: 4475–4488. 11714673

7. Gumienny T, Brugnera E (2001) CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration. Cell 107: 27–41. 11595183

8. Zhou Z, Caron E, Hartwieg E, Hall a, Horvitz HR (2001) The C. elegans PH domain protein CED-12 regulates cytoskeletal reorganization via a Rho/Rac GTPase signaling pathway. Dev Cell 1: 477–489. 11703939

9. Wu YC, Tsai MC, Cheng LC, Chou CJ, Weng NY (2001) C. elegans CED-12 acts in the conserved crkII/DOCK180/Rac pathway to control cell migration and cell corpse engulfment. Dev Cell 1: 491–502. 11703940

10. Reddien P, Horvitz H (2000) CED-2/CrkII and CED-10/Rac control phagocytosis and cell migration in Caenorhabditis elegans. Nat Cell Biol 2: 131–136. 10707082

11. Côté J-F, Vuori K (2007) GEF what? Dock180 and related proteins help Rac to polarize cells in new ways. Trends Cell Biol 17: 383–393. 17765544

12. Gómez-Orte E, Sáenz-Narciso B, Moreno S, Cabello J (2013) Multiple functions of the noncanonical Wnt pathway. Trends Genet 29: 545–553. doi: 10.1016/j.tig.2013.06.003 23846023

13. Levy-Strumpf N, Culotti JG (2007) VAB-8, UNC-73 and MIG-2 regulate axon polarity and cell migration functions of UNC-40 in C. elegans. Nat Neurosci 10: 161–168. 17237777

14. Chan SS, Zheng H, Su MW, Wilk R, Killeen MT, et al. (1996) UNC-40, a C. elegans homolog of DCC (Deleted in Colorectal Cancer), is required in motile cells responding to UNC-6 netrin cues. Cell 87: 187–195. 8861903

15. Hedgecock EM, Culotti JG, Hall DH (1990) The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans. Neuron 4: 61–85. 2310575

16. Rajasekharan S, Kennedy TE (2009) The netrin protein family. Genome Biol 10: 239. doi: 10.1186/gb-2009-10-9-239 19785719

17. Wu Y-C, Cheng T-W, Lee M-C, Weng N-Y (2002) Distinct Rac Activation Pathways Control Caenorhabditis elegans Cell Migration and Axon Outgrowth. Dev Biol 250: 145–155. 12297102

18. Watari-Goshima N, Ogura K, Wolf FW, Goshima Y, Garriga G (2007) C. elegans VAB-8 and UNC-73 regulate the SAX-3 receptor to direct cell and growth-cone migrations. Nat Neurosci 10: 169–176. 17237778

19. Vanderzalm PJ, Pandey A, Hurwitz ME, Bloom L, Horvitz HR, et al. (2009) C. elegans CARMIL negatively regulates UNC-73/Trio function during neuronal development. Development 136: 1201–1210. doi: 10.1242/dev.026666 19244282

20. Dalpé G, Zhang LW, Zheng H, Culotti JG (2004) Conversion of cell movement responses to Semaphorin-1 and Plexin-1 from attraction to repulsion by lowered levels of specific RAC GTPases in C. elegans. Development 131: 2073–2088. 15073148

21. Kishore RS, Sundaram M V (2002) ced-10 Rac and mig-2 function redundantly and act with unc-73 trio to control the orientation of vulval cell divisions and migrations in Caenorhabditis elegans. Dev Biol 241: 339–348. 11784116

22. Zipkin ID, Kindt RM, Kenyon CJ (1997) Role of a new Rho family member in cell migration and axon guidance in C. elegans. Cell 90: 883–894. 9298900

23. Warren CE, Krizus a, Dennis JW (2001) Complementary expression patterns of six nonessential Caenorhabditis elegans core 2/I N-acetylglucosaminyltransferase homologues. Glycobiology 11: 979–988. 11744632

24. Schwabiuk M, Coudiere L, Merz DC (2009) SDN-1/syndecan regulates growth factor signaling in distal tip cell migrations in C. elegans. Dev Biol 334: 235–242. doi: 10.1016/j.ydbio.2009.07.020 19631636

25. Nishiwaki K (1999) Mutations affecting symmetrical migration of distal tip cells in Caenorhabditis elegans. Genetics 152: 985–997. 10388818

26. Geisbrecht ER, Haralalka S, Swanson SK, Florens L, Washburn MP, et al. (2008) Drosophila ELMO/CED-12 interacts with Myoblast city to direct myoblast fusion and ommatidial organization. Dev Biol 314: 137–149. doi: 10.1016/j.ydbio.2007.11.022 18163987

27. Lu M, Ravichandran KS (2006) Dock180-ELMO cooperation in Rac activation. Methods Enzymol 406: 388–402. 16472672

28. Kiyokawa E, Hashimoto Y, Kobayashi S, Sugimura H, Kurata T, et al. (1998) Activation of Rac1 by a Crk SH3-binding protein, DOCK180. Genes Dev 12: 3331–3336. 9808620

29. Killeen M, Tong J, Krizus A, Steven R, Scott I, et al. (2002) UNC-5 Function Requires Phosphorylation of Cytoplasmic Tyrosine 482, but Its UNC-40-Independent Functions also Require a Region between the ZU-5 and Death Domains. Dev Biol 251: 348–366. 12435363

30. Tong J, Killeen M, Steven R, Binns KL, Culotti J, et al. (2001) Netrin stimulates tyrosine phosphorylation of the UNC-5 family of netrin receptors and induces Shp2 binding to the RCM cytodomain. J Biol Chem 276: 40917–40925. 11533026

31. Norris AD, Lundquist E a (2011) UNC-6/netrin and its receptors UNC-5 and UNC-40/DCC modulate growth cone protrusion in vivo in C. elegans. Development 138: 4433–4442. doi: 10.1242/dev.068841 21880785

32. Moore SW, Correia JP, Lai Wing Sun K, Pool M, Fournier AE, et al. (2008) Rho inhibition recruits DCC to the neuronal plasma membrane and enhances axon chemoattraction to netrin 1. Development 135: 2855–2864. doi: 10.1242/dev.024133 18653556

33. Ridley a J (2001) Rho proteins: linking signaling with membrane trafficking. Traffic 2: 303–310. 11350626

34. Ellis S, Mellor H (2000) Regulation of endocytic traffic by rho family GTPases. Trends Cell Biol 10: 85–88. 10675900

35. Witze ES, Litman ES, Argast GM, Moon RT, Ahn NG (2008) Wnt5a control of cell polarity and directional movement by polarized redistribution of adhesion receptors. Science 320: 365–369. doi: 10.1126/science.1151250 18420933

36. Ulrich F, Krieg M, Schötz E-M, Link V, Castanon I, et al. (2005) Wnt11 functions in gastrulation by controlling cell cohesion through Rab5c and E-cadherin. Dev Cell 9: 555–564. 16198297

37. Sun L, Liu O, Desai J, Karbassi F, Sylvain M-A, et al. (2012) CED-10/Rac1 regulates endocytic recycling through the RAB-5 GAP TBC-2. PLoS Genet 8: e1002785. doi: 10.1371/journal.pgen.1002785 22807685

38. Palamidessi A, Frittoli E, Garré M, Faretta M, Mione M, et al. (2008) Endocytic trafficking of Rac is required for the spatial restriction of signaling in cell migration. Cell 134: 135–147. doi: 10.1016/j.cell.2008.05.034 18614017

39. Middelkoop TC, Korswagen HC (2014) Development and migration of the C. elegans Q neuroblasts and their descendants: 1–23. doi: 10.1895/wormbook.1.173.1 25317540

40. Green JL, Inoue T, Sternberg PW (2008) Opposing Wnt pathways orient cell polarity during organogenesis. Cell 134: 646–656. doi: 10.1016/j.cell.2008.06.026 18724937

41. Zinovyeva AY, Yamamoto Y, Sawa H, Forrester WC (2008) Complex network of Wnt signaling regulates neuronal migrations during Caenorhabditis elegans development. Genetics 179: 1357–1371. doi: 10.1534/genetics.108.090290 18622031

42. Freitas C, Larrivée B, Eichmann A (2008) Netrins and UNC5 receptors in angiogenesis. Angiogenesis 11: 23–29. doi: 10.1007/s10456-008-9096-2 18266062

43. Mehlen P, Furne C (2005) Netrin-1: when a neuronal guidance cue turns out to be a regulator of tumorigenesis. Cell Mol Life Sci 62: 2599–2616. 16158190

44. Shimizu A, Nakayama H, Wang P, König C, Akino T, et al. (2013) Netrin-1 promotes glioblastoma cell invasiveness and angiogenesis by multiple pathways including activation of RhoA, cathepsin B, and cAMP-response element-binding protein. J Biol Chem 288: 2210–2222. doi: 10.1074/jbc.M112.397398 23195957

45. Akino T, Han X, Nakayama H, McNeish B, Zurakowski D, et al. (2014) Netrin-1 promotes medulloblastoma cell invasiveness and angiogenesis, and demonstrates elevated expression in tumor tissue and urine of patients with pediatric medulloblastoma. Cancer Res 74: 3716–3726. doi: 10.1158/0008-5472.CAN-13-3116 24812271

46. Morrissey M a, Hagedorn EJ, Sherwood DR (2013) Cell invasion through basement membrane: The netrin receptor DCC guides the way. Worm 2: e26169. doi: 10.4161/worm.26169 24778942

47. Brenner S (1974) The genetics of Caenorhabditis elegans. Genetics 77: 71–94. 4366476

48. Frøkjær-Jensen C, Davis MW, Sarov M, Taylor J, Flibotte S, et al. (2014) Random and targeted transgene insertion in Caenorhabditis elegans using a modified Mos1 transposon. Nat Methods 11: 529–534. doi: 10.1038/nmeth.2889 24820376

49. Timmons L, Fire a (1998) Specific interference by ingested dsRNA. Nature 395: 854. 9804418

50. Fraser AG, Kamath RS, Zipperlen P, Martinez-Campos M, Sohrmann M, et al. (2000) Functional genomic analysis of C. elegans chromosome I by systematic RNA interference. Nature 408: 325–330. 11099033

51. Kamath RS, Martinez-Campos M, Zipperlen P, Fraser AG, Ahringer J (2001) Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biol 2: RESEARCH0002.1–0002.10.

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