Tissue-Specific Gain of RTK Signalling Uncovers Selective Cell Vulnerability during Embryogenesis


The need to achieve precise control of RTK activation is highlighted by human pathologies such as congenital malformations and cancers caused by aberrant RTK signalling. Identifying strategies to restrain RTK activity in cancer and/or to reactivate RTKs for counteracting degenerative processes is the focus of intense research efforts. We designed a genetic system to enhance RTK signalling during mouse embryogenesis in order to examine the competence of cells to deal with changes in RTK inputs. Our data reveal that most embryonic cells are capable of: 1) handling moderate perturbations in Met-RTK expression levels, 2) imposing a threshold of intracellular signalling activation despite elevated Met-RTK inputs, and/or 3) integrating variable quantitative levels of Met-RTK signalling within biological responses. Our results also establish that certain cell types, such as limb mesenchyme, are particularly vulnerable to alterations of the spatial distribution of RTK expression. The vulnerability of limb mesenchyme to enhanced Met levels is illustrated by gene expression changes, by interference with HGF chemoattractant effects, and by loss of accessibility to incoming myoblasts, leading to limb muscle defects. These findings highlight how resilience versus vulnerability to RTK fluctuation is strictly linked to cell competence and to the robustness of the developmental programs they undergo.


Vyšlo v časopise: Tissue-Specific Gain of RTK Signalling Uncovers Selective Cell Vulnerability during Embryogenesis. PLoS Genet 11(9): e32767. doi:10.1371/journal.pgen.1005533
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005533

Souhrn

The need to achieve precise control of RTK activation is highlighted by human pathologies such as congenital malformations and cancers caused by aberrant RTK signalling. Identifying strategies to restrain RTK activity in cancer and/or to reactivate RTKs for counteracting degenerative processes is the focus of intense research efforts. We designed a genetic system to enhance RTK signalling during mouse embryogenesis in order to examine the competence of cells to deal with changes in RTK inputs. Our data reveal that most embryonic cells are capable of: 1) handling moderate perturbations in Met-RTK expression levels, 2) imposing a threshold of intracellular signalling activation despite elevated Met-RTK inputs, and/or 3) integrating variable quantitative levels of Met-RTK signalling within biological responses. Our results also establish that certain cell types, such as limb mesenchyme, are particularly vulnerable to alterations of the spatial distribution of RTK expression. The vulnerability of limb mesenchyme to enhanced Met levels is illustrated by gene expression changes, by interference with HGF chemoattractant effects, and by loss of accessibility to incoming myoblasts, leading to limb muscle defects. These findings highlight how resilience versus vulnerability to RTK fluctuation is strictly linked to cell competence and to the robustness of the developmental programs they undergo.


Zdroje

1. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117–34. doi: 10.1016/j.cell.2010.06.011 20602996

2. Casaletto JB, McClatchey AI. Spatial regulation of receptor tyrosine kinases in development and cancer. Nat Rev Cancer. 2012;12(6):387–400. doi: 10.1038/nrc3277 22622641

3. Bache KG, Slagsvold T, Stenmark H. Defective downregulation of receptor tyrosine kinases in cancer. Embo J. 2004;23(14):2707–12. 15229652

4. Maina F. Strategies to overcome drug resistance of receptor tyrosine kinaseaddicted cancer cells. Current medicinal chemistry. 2014;21(14):1607–17. 23992334

5. Flores GV, Duan H, Yan H, Nagaraj R, Fu W, Zou Y, et al. Combinatorial signaling in the specification of unique cell fates. Cell. 2000;103(1):75–85. 11051549

6. de Celis JF, Bray S, Garcia-Bellido A. Notch signalling regulates veinlet expression and establishes boundaries between veins and interveins in the Drosophila wing. Development. 1997;124(10):1919–28. 9169839

7. Li J, Li WX. Drosophila gain-of-function mutant RTK torso triggers ectopic Dpp and STAT signaling. Genetics. 2003;164(1):247–58. 12750336

8. Trusolino L, Bertotti A, Comoglio PM. MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol. 2010;11(12):834–48. doi: 10.1038/nrm3012 21102609

9. Huh CG, Factor VM, Sanchez A, Uchida K, Conner EA, Thorgeirsson SS. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci U S A. 2004;101(13):4477–82. 15070743.

10. Calvi C, Podowski M, Lopez-Mercado A, Metzger S, Misono K, Malinina A, et al. Hepatocyte growth factor, a determinant of airspace homeostasis in the murine lung. PLoS genetics. 2013;9(2):e1003228. doi: 10.1371/journal.pgen.1003228 23459311;

11. Chmielowiec J, Borowiak M, Morkel M, Stradal T, Munz B, Werner S, et al. c-Met is essential for wound healing in the skin. J Cell Biol. 2007;177(1):151–62. 17403932

12. Knudsen BS, Vande Woude G. Showering c-MET-dependent cancers with drugs. Curr Opin Genet Dev. 2008;18(1):87–96. doi: 10.1016/j.gde.2008.02.001 18406132

13. Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G. Targeting MET in cancer: rationale and progress. Nat Rev Cancer. 2012;12(2):89–103. Epub 2012/01/25. doi: 10.1038/nrc3205 22270953

14. Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487(7408):500–4. doi: 10.1038/nature11183 22763439

15. Bladt F, Riethmacher D, Isenmann S, Aguzzi A, Birchmeier C. Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature. 1995;376:768–71. 7651534

16. Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschlesche W, Sharpe M, et al. Scatter factor/hepatocyte growth factor is essential for liver development. Nature. 1995;373:699–702. 7854452

17. Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T, et al. Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature. 1995;373:702–5. 7854453

18. Maina F, Casagranda F, Audero E, Simeone A, Comoglio P, Klein R, et al. Uncoupling of Grb2 from the Met receptor in vivo reveals complex roles in muscle development. Cell. 1996;87:531–42. 8898205

19. Maina F, Hilton MC, Andres R, Wyatt S, Klein R, Davies AM. Multiple roles for hepatocyte growth factor in sympathetic neuron development. Neuron. 1998;20:835–46. 9620689

20. Maina F, Hilton MC, Ponzetto C, Davies AM, Klein R. Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons. Genes and Development. 1997;11:3341–50. 9407027

21. Maina F, Klein R. Hepatocyte growth factor—a versatile signal for developing neurons. Nature Neuroscience. 1999;2:213–7. 10195212

22. Lamballe F, Genestine M, Caruso N, Arce V, Richelme S, Helmbacher F, et al. Pool-specific regulation of motor neuron survival by neurotrophic support. J Neurosci. 2011;31(31):11144–58. doi: 10.1523/JNEUROSCI.2198-11.2011 21813676

23. Caruso N, Herberth B, Lamballe F, Arce-Gorvel V, Maina F, Helmbacher F. Plasticity versus specificity in RTK signalling modalities for distinct biological outcomes in motor neurons. BMC Biol. 2014;12(1):56.

24. Genestine M, Caricati E, Fico A, Richelme S, Hassani H, Sunyach C, et al. Enhanced neuronal Met signalling levels in ALS mice delay disease onset. Cell Death Dis. 2011;2:e130. doi: 10.1038/cddis.2011.11 21412276

25. Tonges L, Ostendorf T, Lamballe F, Genestine M, Dono R, Koch JC, et al. Hepatocyte growth factor protects retinal ganglion cells by increasing neuronal survival and axonal regeneration in vitro and in vivo. J Neurochem. 2011;117(5):892–903. 21443522. doi: 10.1111/j.1471-4159.2011.07257.x

26. Schwenk F, Baron U, Rajewsky K. A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res. 1995;23:5080–1. 8559668

27. Kelly R, Alonso S, Tajbakhsh S, Cossu G, Buckingham M. Myosin light chain 3F regulatory sequences confer regionalized cardiac and skeletal muscle expression in transgenic mice. J Cell Biol. 1995;129(2):383–96. Epub 1995/04/01. 7721942

28. Maina F, Pante G, Helmbacher F, Andres R, Porthin A, Davies AM, et al. Coupling Met to specific pathways results in distinct developmental outcomes. Mol Cell. 2001;7(6):1293–306. 11430831

29. Buckingham M, Rigby PW. Gene regulatory networks and transcriptional mechanisms that control myogenesis. Dev Cell. 2014;28(3):225–38. doi: 10.1016/j.devcel.2013.12.020 24525185

30. Engleka KA, Gitler AD, Zhang M, Zhou DD, High FA, Epstein JA. Insertion of Cre into the Pax3 locus creates a new allele of Splotch and identifies unexpected Pax3 derivatives. Dev Biol. 2005;280(2):396–406. Epub 2005/05/11. 15882581

31. Logan M, Martin JF, Nagy A, Lobe C, Olson EN, Tabin CJ. Expression of Cre Recombinase in the developing mouse limb bud driven by a Prxl enhancer. Genesis. 2002;33(2):77–80. Epub 2002/07/12. 12112875

32. Luxardi G, Galli A, Forlani S, Lawson K, Maina F, Dono R. Glypicans are differentially expressed during patterning and neurogenesis of early mouse brain. Biochem Biophys Res Commun. 2007;352(1):55–60. 17107664

33. Fico A, de Chevigny A, Egea J, Bosl MR, Cremer H, Maina F, et al. Modulating Glypican4 Suppresses Tumorigenicity of Embryonic Stem Cells while Preserving Self-Renewal and Pluripotency. Stem Cells. 2012. Epub 2012/07/05.

34. Fico A, de Chevigny A, Melon C, Bohic M, Kerkerian-Le Goff L, Maina F, et al. Reducing glypican-4 in ES cells improves recovery in a rat model of Parkinson's disease by increasing the production of dopaminergic neurons and decreasing teratoma formation. J Neurosci. 2014;34(24):8318–23. doi: 10.1523/JNEUROSCI.2501-13.2014 24920634

35. Tkachenko E, Rhodes JM, Simons M. Syndecans: new kids on the signaling block. Circ Res. 2005;96(5):488–500. 15774861

36. Wang X, Page-McCaw A. A matrix metalloproteinase mediates long-distance attenuation of stem cell proliferation. J Cell Biol. 2014;206(7):923–36. doi: 10.1083/jcb.201403084 25267296

37. Hacker U, Nybakken K, Perrimon N. Heparan sulphate proteoglycans: the sweet side of development. Nat Rev Mol Cell Biol. 2005;6(7):530–41. 16072037

38. Kakugawa S, Langton PF, Zebisch M, Howell SA, Chang TH, Liu Y, et al. Notum deacylates Wnt proteins to suppress signalling activity. Nature. 2015;519(7542):187–92. doi: 10.1038/nature14259 25731175

39. Karihaloo A, Kale S, Rosenblum ND, Cantley LG. Hepatocyte growth factor-mediated renal epithelial branching morphogenesis is regulated by glypican-4 expression. Mol Cell Biol. 2004;24(19):8745–52. 15367691

40. Cecchi F, Pajalunga D, Fowler CA, Uren A, Rabe DC, Peruzzi B, et al. Targeted disruption of heparan sulfate interaction with hepatocyte and vascular endothelial growth factors blocks normal and oncogenic signaling. Cancer Cell. 2012;22(2):250–62. doi: 10.1016/j.ccr.2012.06.029 22897854

41. Derksen PW, Keehnen RM, Evers LM, van Oers MH, Spaargaren M, Pals ST. Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma. Blood. 2002;99(4):1405–10. 11830493

42. Pante G, Thompson J, Lamballe F, Iwata T, Ferby I, Barr FA, et al. Mitogen-inducible gene 6 is an endogenous inhibitor of HGF/Met-induced cell migration and neurite growth. J Cell Biol. 2005;171(2):337–48. 16247031

43. Gerritsen ME, Tomlinson JE, Zlot C, Ziman M, Hwang S. Using gene expression profiling to identify the molecular basis of the synergistic actions of hepatocyte growth factor and vascular endothelial growth factor in human endothelial cells. Br J Pharmacol. 2003;140(4):595–610. Epub 2003/09/25. 14504135

44. Factor VM, Seo D, Ishikawa T, Kaposi-Novak P, Marquardt JU, Andersen JB, et al. Loss of c-Met disrupts gene expression program required for G2/M progression during liver regeneration in mice. PLoS One. 2010;5(9). Epub 2010/09/24.

45. Vasyutina E, Stebler J, Brand-Saberi B, Schulz S, Raz E, Birchmeier C. CXCR4 and Gab1 cooperate to control the development of migrating muscle progenitor cells. Genes Dev. 2005;19(18):2187–98. 16166380

46. Moumen A, Ieraci A, Patane S, Sole C, Comella JX, Dono R, et al. Met signals hepatocyte survival by preventing Fas-triggered FLIP degradation in a PI3k-Akt-dependent manner. Hepatology. 2007;45(5):1210–7. 17464994.

47. Moumen A, Patane S, Porras A, Dono R, Maina F. Met acts on Mdm2 via mTOR to signal cell survival during development. Development. 2007;134(7):1443–51. 17329361

48. Furlan A, Lamballe F, Stagni V, Hussain A, Richelme S, Prodosmo A, et al. Met acts through Abl to regulate p53 transcriptional outcomes and cell survival in the developing liver. J Hepatol. 2012;57(6):1292–8. Epub 2012/08/15. doi: 10.1016/j.jhep.2012.07.044 22889954

49. Patane S, Pietrancosta N, Hassani H, Leroux V, Maigret B, Kraus JL, et al. A new Met inhibitory-scaffold identified by a focused forward chemical biological screen. Biochem Biophys Res Commun. 2008;375(2):184–9. doi: 10.1016/j.bbrc.2008.07.159 18703015

50. Furlan A, Colombo F, Kover A, Issaly N, Tintori C, Angeli L, et al. Identification of new aminoacid amides containing the imidazo[2,1-b]benzothiazol-2-ylphenyl moiety as inhibitors of tumorigenesis by oncogenic Met signaling. Eur J Med Chem. 2012;47(1):239–54. Epub 2011/12/06. doi: 10.1016/j.ejmech.2011.10.051 22138308

51. Relaix F, Polimeni M, Rocancourt D, Ponzetto C, Schafer BW, Buckingham M. The transcriptional activator PAX3-FKHR rescues the defects of Pax3 mutant mice but induces a myogenic gain-of-function phenotype with ligand-independent activation of Met signaling in vivo. Genes Dev. 2003;17(23):2950–65. 14665670

52. Gutierrez J, Cabrera D, Brandan E. Glypican-1 regulates myoblast response to HGF via Met in a lipid raft-dependent mechanism: effect on migration of skeletal muscle precursor cells. Skeletal muscle. 2014;4(1):5. doi: 10.1186/2044-5040-4-5 24517345

53. Cornelison DD, Filla MS, Stanley HM, Rapraeger AC, Olwin BB. Syndecan-3 and syndecan-4 specifically mark skeletal muscle satellite cells and are implicated in satellite cell maintenance and muscle regeneration. Dev Biol. 2001;239(1):79–94. Epub 2002/01/11. 11784020

54. Lee SJ, Huynh TV, Lee YS, Sebald SM, Wilcox-Adelman SA, Iwamori N, et al. Role of satellite cells versus myofibers in muscle hypertrophy induced by inhibition of the myostatin/activin signaling pathway. Proc Natl Acad Sci U S A. 2012;109(35):E2353–60. Epub 2012/08/08. doi: 10.1073/pnas.1206410109 22869749

55. Rodgers JT, King KY, Brett JO, Cromie MJ, Charville GW, Maguire KK, et al. mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert). Nature. 2014;510(7505):393–6. doi: 10.1038/nature13255 24870234

56. Caruso N, Herberth B, Bartoli M, Puppo F, Dumonceaux J, Zimmermann A, et al. Deregulation of the protocadherin gene FAT1 alters muscle shapes: implications for the pathogenesis of facioscapulohumeral dystrophy. PLoS genetics. 2013;9(6):e1003550. doi: 10.1371/journal.pgen.1003550 23785297

57. Barber TD, Barber MC, Tomescu O, Barr FG, Ruben S, Friedman TB. Identification of target genes regulated by PAX3 and PAX3-FKHR in embryogenesis and alveolar rhabdomyosarcoma. Genomics. 2002;79(3):278–84. Epub 2002/02/28. 11863357

58. Crepaldi T, Bersani F, Scuoppo C, Accornero P, Prunotto C, Taulli R, et al. Conditional activation of MET in differentiated skeletal muscle induces atrophy. J Biol Chem. 2007;282(9):6812–22. 17194700

59. Takayama H, La Rochelle WJ, Anver M, Bockman DE, Merlino G. Scatter factor/hepatocyte growth factor as a regulator of skeletal muscle and neural crest development. Proc Natl Acad Sci U S A. 1996;93(12):5866–71. 8650184

60. Takayama H, LaRochelle WJ, Sharp R, Otsuka T, Kriebel P, Anver M, et al. Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. Proc Natl Acad Sci U S A. 1997;94(2):701–6. 9012848

61. Dono R, Texido G, Dussel R, Ehmke H, Zeller R. Impaired cerebral cortex development and blood pressure regulation in FGF-2-deficient mice. EMBO J. 1998;17(15):4213–25. 9687490

62. Mesbah K, Harrelson Z, Theveniau-Ruissy M, Papaioannou VE, Kelly RG. Tbx3 is required for outflow tract development. Circ Res. 2008;103(7):743–50. doi: 10.1161/CIRCRESAHA.108.172858 18723448

63. Furlan A, Roux B, Lamballe F, Conti F, Issaly N, Daian F, et al. Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures. PLoS One. 2012;7(10):e46738. Epub 2012/10/17. doi: 10.1371/journal.pone.0046738 23071625

64. Furlan A, Stagni V, Hussain A, Richelme S, Conti F, Prodosmo A, et al. Abl interconnects oncogenic Met and p53 core pathways in cancer cells. Cell Death Differ. 2011;18(10):1608–16. Epub 2011/04/02. doi: 10.1038/cdd.2011.23 21455220

65. Blitz E, Viukov S, Sharir A, Shwartz Y, Galloway JL, Pryce BA, et al. Bone ridge patterning during musculoskeletal assembly is mediated through SCX regulation of Bmp4 at the tendon-skeleton junction. Dev Cell. 2009;17(6):861–73. doi: 10.1016/j.devcel.2009.10.010 20059955

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