Hepatocyte Growth Factor Signaling in Intrapancreatic Ductal Cells Drives Pancreatic Morphogenesis

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In a forward genetic screen for regulators of pancreas development in zebrafish, we identified donut^s908, a mutant which exhibits failed outgrowth of the exocrine pancreas. The s908 mutation leads to a leucine to arginine substitution in the ectodomain of the hepatocyte growth factor (HGF) tyrosine kinase receptor, Met. This missense mutation impedes the proteolytic maturation of the receptor, its trafficking to the plasma membrane, and diminishes the phospho-activation of its kinase domain. Interestingly, during pancreatogenesis, met and its hgf ligands are expressed in pancreatic epithelia and mesenchyme, respectively. Although Met signaling elicits mitogenic and migratory responses in varied contexts, normal proliferation rates in donut mutant pancreata together with dysmorphic, mislocalized ductal cells suggest that met primarily functions motogenically in pancreatic tail formation. Treatment with PI3K and STAT3 inhibitors, but not with MAPK inhibitors, phenocopies the donut pancreatic defect, further indicating that Met signals through migratory pathways during pancreas development. Chimera analyses showed that Met-deficient cells were excluded from the duct, but not acinar, compartment in the pancreatic tail. Conversely, wild-type intrapancreatic duct and “tip cells” at the leading edge of the growing pancreas rescued the donut phenotype. Altogether, these results reveal a novel and essential role for HGF signaling in the intrapancreatic ducts during exocrine morphogenesis.

Vyšlo v časopise: Hepatocyte Growth Factor Signaling in Intrapancreatic Ductal Cells Drives Pancreatic Morphogenesis. PLoS Genet 9(7): e32767. doi:10.1371/journal.pgen.1003650
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003650

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1. FieldHA, OberEA, RoeserT, StainierDY (2003) Formation of the digestive system in zebrafish. I. Liver morphogenesis. Dev Biol 253: 279–290.

2. NiemannHH, GherardiE, BleymullerWM, HeinzDW (2012) Engineered variants of InlB with an additional leucine-rich repeat discriminate between physiologically relevant and packing contacts in crystal structures of the InlB:MET complex. Protein Sci 21: 1528–1539.

3. WardAB, WargaRM, PrinceVE (2007) Origin of the zebrafish endocrine and exocrine pancreas. Dev Dyn 236: 1558–1569.

4. BiemarF, ArgentonF, SchmidtkeR, EpperleinS, PeersB, et al. (2001) Pancreas development in zebrafish: early dispersed appearance of endocrine hormone expressing cells and their convergence to form the definitive islet. Dev Biol 230: 189–203.

5. FieldHA, DongPD, BeisD, StainierDY (2003) Formation of the digestive system in zebrafish. II. Pancreas morphogenesis. Dev Biol 261: 197–208.

6. PaulsS, ZecchinE, TisoN, BortolussiM, ArgentonF (2007) Function and regulation of zebrafish nkx2.2a during development of pancreatic islet and ducts. Dev Biol 304: 875–890.

7. YeeNS, LorentK, PackM (2005) Exocrine pancreas development in zebrafish. Dev Biol 284: 84–101.

8. LandsmanL, NijagalA, WhitchurchTJ, VanderlaanRL, ZimmerWE, et al. (2011) Pancreatic mesenchyme regulates epithelial organogenesis throughout development. PLoS Biol 9: e1001143.

9. SerupP (2012) Signaling pathways regulating murine pancreatic development. Semin Cell Dev Biol 23: 663–672.

10. GherardiE, BirchmeierW, BirchmeierC, Vande WoudeG (2012) Targeting MET in cancer: rationale and progress. Nat Rev Cancer 12: 89–103.

11. BladtF, RiethmacherD, IsenmannS, AguzziA, BirchmeierC (1995) Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature 376: 768–771.

12. HainesL, NeytC, GautierP, KeenanDG, Bryson-RichardsonRJ, et al. (2004) Met and Hgf signaling controls hypaxial muscle and lateral line development in the zebrafish. Development 131: 4857–4869.

13. SchmidtC, BladtF, GoedeckeS, BrinkmannV, ZschiescheW, et al. (1995) Scatter factor/hepatocyte growth factor is essential for liver development. Nature 373: 699–702.

14. UeharaY, MinowaO, MoriC, ShiotaK, KunoJ, et al. (1995) Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature 373: 702–705.

15. JohanssonM, MattssonG, AnderssonA, JanssonL, CarlssonPO (2006) Islet endothelial cells and pancreatic beta-cell proliferation: studies in vitro and during pregnancy in adult rats. Endocrinology 147: 2315–2324.

16. SonnenbergE, MeyerD, WeidnerKM, BirchmeierC (1993) Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development. J Cell Biol 123: 223–235.

17. DemirciC, ErnstS, Alvarez-PerezJC, RosaT, ValleS, et al. (2012) Loss of HGF/c-Met signaling in pancreatic beta-cells leads to incomplete maternal beta-cell adaptation and gestational diabetes mellitus. Diabetes 61: 1143–1152.

18. Mellado-GilJ, RosaTC, DemirciC, Gonzalez-PertusaJA, Velazquez-GarciaS, et al. (2011) Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic beta-cell death and accelerates the onset of diabetes. Diabetes 60: 525–536.

19. AparicioIM, Garcia-MarinLJ, AndreolottiAG, BodegaG, JensenRT, et al. (2003) Hepatocyte growth factor activates several transduction pathways in rat pancreatic acini. Biochim Biophys Acta 1643: 37–46.

20. AndersonRM, BoschJA, GollMG, HesselsonD, DongPD, et al. (2009) Loss of Dnmt1 catalytic activity reveals multiple roles for DNA methylation during pancreas development and regeneration. Dev Biol 334: 213–223.

21. GodinhoL, MummJS, WilliamsPR, SchroeterEH, KoerberA, et al. (2005) Targeting of amacrine cell neurites to appropriate synaptic laminae in the developing zebrafish retina. Development 132: 5069–5079.

22. BasilicoC, ArnesanoA, GalluzzoM, ComoglioPM, MichieliP (2008) A high affinity hepatocyte growth factor-binding site in the immunoglobulin-like region of Met. J Biol Chem 283: 21267–21277.

23. GherardiE, YoulesME, MiguelRN, BlundellTL, IameleL, et al. (2003) Functional map and domain structure of MET, the product of the c-met protooncogene and receptor for hepatocyte growth factor/scatter factor. Proc Natl Acad Sci U S A 100: 12039–12044.

24. BirchmeierC, BirchmeierW, GherardiE, Vande WoudeGF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4: 915–925.

25. KomadaM, KitamuraN (1993) The cell dissociation and motility triggered by scatter factor/hepatocyte growth factor are mediated through the cytoplasmic domain of the c-Met receptor. Oncogene 8: 2381–2390.

26. MarkMR, LokkerNA, ZioncheckTF, LuisEA, GodowskiPJ (1992) Expression and characterization of hepatocyte growth factor receptor-IgG fusion proteins. Effects of mutations in the potential proteolytic cleavage site on processing and ligand binding. J Biol Chem 267: 26166–26171.

27. KomadaM, HatsuzawaK, ShibamotoS, ItoF, NakayamaK, et al. (1993) Proteolytic processing of the hepatocyte growth factor/scatter factor receptor by furin. FEBS Lett 328: 25–29.

28. ShapiroJ, SciakyN, LeeJ, BosshartH, AngelettiRH, et al. (1997) Localization of endogenous furin in cultured cell lines. J Histochem Cytochem 45: 3–12.

29. KikuchiY, AgathonA, AlexanderJ, ThisseC, WaldronS, et al. (2001) casanova encodes a novel Sox-related protein necessary and sufficient for early endoderm formation in zebrafish. Genes Dev 15: 1493–1505.

30. StaffordD, WhiteRJ, KinkelMD, LinvilleA, SchillingTF, et al. (2006) Retinoids signal directly to zebrafish endoderm to specify insulin-expressing beta-cells. Development 133: 949–956.

31. HidalgoM (2012) New insights into pancreatic cancer biology. Ann Oncol 23 Suppl 10: x135–138.

32. LloydRV, HardinH, Montemayor-GarciaC, RotondoF, SyroLV, et al. (2013) Stem cells and cancer stem-like cells in endocrine tissues. Endocr Pathol 24: 1–10.

33. Westerfield M, editor (2000) The zebrafish book. A guide for the laboratory use of zebrafish (Danio rerio). Eugene: Univ. of Oregon Press.

34. FarooqM, SulochanaKN, PanX, ToJ, ShengD, et al. (2008) Histone deacetylase 3 (hdac3) is specifically required for liver development in zebrafish. Dev Biol 317: 336–353.

35. CuradoS, AndersonRM, JungblutB, MummJ, SchroeterE, et al. (2007) Conditional targeted cell ablation in zebrafish: a new tool for regeneration studies. Dev Dyn 236: 1025–1035.

36. ShinCH, ChungWS, HongSK, OberEA, VerkadeH, et al. (2008) Multiple roles for Med12 in vertebrate endoderm development. Dev Biol 317: 467–479.

37. HesselsonD, AndersonRM, BeinatM, StainierDY (2009) Distinct populations of quiescent and proliferative pancreatic beta-cells identified by HOTcre mediated labeling. Proc Natl Acad Sci U S A 106: 14896–14901.

38. KikuchiY, VerkadeH, ReiterJF, KimCH, ChitnisAB, et al. (2004) Notch signaling can regulate endoderm formation in zebrafish. Dev Dyn 229: 756–762.

39. KimJH, LeeSR, LiLH, ParkHJ, ParkJH, et al. (2011) High cleavage efficiency of a 2A peptide derived from porcine teschovirus-1 in human cell lines, zebrafish and mice. PLoS One 6: e18556.

40. ThermesV, GrabherC, RistoratoreF, BourratF, ChoulikaA, et al. (2002) I-SceI meganuclease mediates highly efficient transgenesis in fish. Mech Dev 118: 91–98.

41. GherardiE, SandinS, PetoukhovMV, FinchJ, YoulesME, et al. (2006) Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc Natl Acad Sci U S A 103: 4046–4051.

42. ChungWS, StainierDY (2008) Intra-endodermal interactions are required for pancreatic beta cell induction. Dev Cell 14: 582–593.

43. DelousM, HellmanNE, GaudeHM, SilbermannF, Le BivicA, et al. (2009) Nephrocystin-1 and nephrocystin-4 are required for epithelial morphogenesis and associate with PALS1/PATJ and Par6. Hum Mol Genet 18: 4711–4723.

44. ElsenGE, ChoiLY, PrinceVE, HoRK (2009) The autism susceptibility gene met regulates zebrafish cerebellar development and facial motor neuron migration. Dev Biol 335: 78–92.