Regulation of Contributes to the Lineage Potential of Neurogenin3+ Endocrine Precursor Cells in the Pancreas

English version České info

During pancreatic development, transcription factor cascades gradually commit precursor populations to the different endocrine cell fate pathways. Although mutational analyses have defined the functions of many individual pancreatic transcription factors, the integrative transcription factor networks required to regulate lineage specification, as well as their sites of action, are poorly understood. In this study, we investigated where and how the transcription factors Nkx2.2 and Neurod1 genetically interact to differentially regulate endocrine cell specification. In an Nkx2.2 null background, we conditionally deleted Neurod1 in the Pdx1+ pancreatic progenitor cells, the Neurog3+ endocrine progenitor cells, or the glucagon+ alpha cells. These studies determined that, in the absence of Nkx2.2 activity, removal of Neurod1 from the Pdx1+ or Neurog3+ progenitor populations is sufficient to reestablish the specification of the PP and epsilon cell lineages. Alternatively, in the absence of Nkx2.2, removal of Neurod1 from the Pdx1+ pancreatic progenitor population, but not the Neurog3+ endocrine progenitor cells, restores alpha cell specification. Subsequent in vitro reporter assays demonstrated that Nkx2.2 represses Neurod1 in alpha cells. Based on these findings, we conclude that, although Nkx2.2 and Neurod1 are both necessary to promote beta cell differentiation, Nkx2.2 must repress Neurod1 in a Pdx1+ pancreatic progenitor population to appropriately commit a subset of Neurog3+ endocrine progenitor cells to the alpha cell lineage. These results are consistent with the proposed idea that Neurog3+ endocrine progenitor cells represent a heterogeneous population of unipotent cells, each restricted to a particular endocrine lineage.

Vyšlo v časopise: Regulation of Contributes to the Lineage Potential of Neurogenin3+ Endocrine Precursor Cells in the Pancreas. PLoS Genet 9(2): e32767. doi:10.1371/journal.pgen.1003278
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003278

Souhrn

Zdroje

1. D'AmourKA, BangAG, EliazerS, KellyOG, AgulnickAD, et al. (2006) Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 24: 1392–1401.

2. KroonE, MartinsonLA, KadoyaK, BangAG, KellyOG, et al. (2008) Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 26: 443–452.

3. NostroMC, SarangiF, OgawaS, HoltzingerA, CorneoB, et al. (2011) Stage-specific signaling through TGFbeta family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells. Development 138: 861–871.

4. GradwohlG, DierichA, LeMeurM, GuillemotF (2000) neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci U S A 97: 1607–1611.

5. GuG, DubauskaiteJ, MeltonDA (2002) Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 129: 2447–2457.

6. HellerRS, JennyM, CollombatP, MansouriA, TomasettoC, et al. (2005) Genetic determinants of pancreatic epsilon-cell development. Dev Biol 286: 217–224.

7. DesgrazR, HerreraPL (2009) Pancreatic neurogenin 3-expressing cells are unipotent islet precursors. Development 136: 3567–3574.

8. CollombatP, Hecksher-SorensenJ, KrullJ, BergerJ, RiedelD, et al. (2007) Embryonic endocrine pancreas and mature beta cells acquire alpha and PP cell phenotypes upon Arx misexpression. J Clin Invest 117: 961–970.

9. JohanssonKA, DursunU, JordanN, GuG, BeermannF, et al. (2007) Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types. Dev Cell 12: 457–465.

10. YangYP, ThorelF, BoyerDF, HerreraPL, WrightCV (2011) Context-specific alpha -to-beta cell reprogramming by forced Pdx1 expression. Genes Dev 25.

11. JorgensenMC, Ahnfelt-RonneJ, HaldJ, MadsenOD, SerupP, et al. (2007) An illustrated review of early pancreas development in the mouse. Endocr Rev 28: 685–705.

12. SusselL, KalamarasJ, Hartigan-O'ConnorDJ, MenesesJJ, PedersenRA, et al. (1998) Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development 125: 2213–2221.

13. ArnesL, LeclercK, FrielJM, HipkensSB, MagnusonMA, et al. (2012) Generation of Nkx2.2:lacZ mice using recombination-mediated cassette exchange technology. Genesis

14. PapizanJB, SingerRA, TschenSI, DhawanS, FrielJM, et al. (2011) Nkx2.2 repressor complex regulates islet beta-cell specification and prevents beta-to-alpha-cell reprogramming. Genes Dev 25: 2291–2305.

15. DasenJS, TiceBC, Brenner-MortonS, JessellTM (2005) A Hox regulatory network establishes motor neuron pool identity and target-muscle connectivity. Cell 123: 477–491.

16. KitamuraT, KitamuraYI, FunahashiY, ShawberCJ, CastrillonDH, et al. (2007) A Foxo/Notch pathway controls myogenic differentiation and fiber type specification. J Clin Invest 117: 2477–2485.

17. LiH, de FariaJP, AndrewP, NitarskaJ, RichardsonWD (2011) Phosphorylation regulates OLIG2 cofactor choice and the motor neuron-oligodendrocyte fate switch. Neuron 69: 918–929.

18. MeadowsSM, MyersCT, KriegPA (2011) Regulation of endothelial cell development by ETS transcription factors. Semin Cell Dev Biol 22: 976–984.

19. CollombatP, MansouriA, Hecksher-SorensenJ, SerupP, KrullJ, et al. (2003) Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes Dev 17: 2591–2603.

20. MellitzerG, BonneS, LucoRF, Van De CasteeleM, Lenne-SamuelN, et al. (2006) IA1 is NGN3-dependent and essential for differentiation of the endocrine pancreas. Embo J 25: 1344–1352.

21. SchafferAE, FreudeKK, NelsonSB, SanderM (2010) Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors. Dev Cell 18: 1022–1029.

22. CollombatP, Hecksher-SorensenJ, BroccoliV, KrullJ, PonteI, et al. (2005) The simultaneous loss of Arx and Pax4 genes promotes a somatostatin-producing cell fate specification at the expense of the alpha- and beta-cell lineages in the mouse endocrine pancreas. Development 132: 2969–2980.

23. KordowichS, CollombatP, MansouriA, SerupP (2011) Arx and Nkx2.2 compound deficiency redirects pancreatic alpha- and beta-cell differentiation to a somatostatin/ghrelin co-expressing cell lineage. BMC Dev Biol 11: 52.

24. MastracciTL, WilcoxCL, PaneaC, GoldenJA, MayCL, et al. (2011) Nkx2.2 and Arx genetically interact to regulate pancreatic endocrine cell development and endocrine hormone expression. Dev Biol 359: 1–11.

25. ChaoCS, LoomisZL, LeeJE, SusselL (2007) Genetic identification of a novel NeuroD1 function in the early differentiation of islet alpha, PP and epsilon cells. Dev Biol 312: 523–532.

26. NayaFJ, HuangHP, QiuY, MutohH, DeMayoFJ, et al. (1997) Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev 11: 2323–2334.

27. PradoCL, Pugh-BernardAE, ElghaziL, Sosa-PinedaB, SusselL (2004) Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci U S A 101: 2924–2929.

28. AndersonKR, TorresCA, SolomonK, BeckerTC, NewgardCB, et al. (2009) Cooperative transcriptional regulation of the essential pancreatic islet gene NeuroD1 (beta2) by Nkx2.2 and neurogenin 3. J Biol Chem 284: 31236–31248.

29. HingoraniSR, PetricoinEF, MaitraA, RajapakseV, KingC, et al. (2003) Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4: 437–450.

30. GuC, SteinGH, PanN, GoebbelsS, HornbergH, et al. (2011) Pancreatic beta cells require NeuroD to achieve and maintain functional maturity. Cell Metab 11: 298–310.

31. SchonhoffSE, Giel-MoloneyM, LeiterAB (2004) Neurogenin 3-expressing progenitor cells in the gastrointestinal tract differentiate into both endocrine and non-endocrine cell types. Dev Biol 270: 443–454.

32. HerreraPL (2000) Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 127: 2317–2322.

33. GasaR, MrejenC, LynnFC, Skewes-CoxP, SanchezL, et al. (2008) Induction of pancreatic islet cell differentiation by the neurogenin-neuroD cascade. Differentiation 76: 381–391.

34. HuangHP, LiuM, El-HodiriHM, ChuK, JamrichM, et al. (2000) Regulation of the pancreatic islet-specific gene BETA2 (neuroD) by neurogenin 3. Mol Cell Biol 20: 3292–3307.

35. MiyataT, MaedaT, LeeJE (1999) NeuroD is required for differentiation of the granule cells in the cerebellum and hippocampus. Genes Dev 13: 1647–1652.

36. Pictet R, Rutter WJ (1972) Development of the embryonic endocrine pancreas; Steiner DF, Frenkel N, editors. Washington, DC: Williams and Wilkins. 25–66 p.

37. SeymourPA, FreudeKK, DuboisCL, ShihHP, PatelNA, et al. (2008) A dosage-dependent requirement for Sox9 in pancreatic endocrine cell formation. Dev Biol 323: 19–30.

38. PanFC, WrightC (2011) Pancreas organogenesis: from bud to plexus to gland. Dev Dyn 240: 530–565.

39. ThorelF, NepoteV, AvrilI, KohnoK, DesgrazR, et al. (2010) Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464: 1149–1154.

40. MastracciTL, SusselL (2012) The Endocrine Pancreas: insights into development, differentiation and diabetes. WIREs Dev Biol doi:10.1002/wdev.44.

41. WangS, Hecksher-SorensenJ, XuY, ZhaoA, DorY, et al. (2008) Myt1 and Ngn3 form a feed-forward expression loop to promote endocrine islet cell differentiation. Dev Biol 317: 531–540.

42. GoebbelsS, BodeU, PieperA, FunfschillingU, SchwabMH, et al. (2005) Cre/loxP-mediated inactivation of the bHLH transcription factor gene NeuroD/BETA2. Genesis 42: 247–252.

43. MadisenL, ZwingmanTA, SunkinSM, OhSW, ZariwalaHA, et al. (2010) A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 13: 133–140.

44. SorianoP (1999) Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 21: 70–71.

45. LarssonLI, MadsenOD, SerupP, JonssonJ, EdlundH (1996) Pancreatic-duodenal homeobox 1 -role in gastric endocrine patterning. Mech Dev 60: 175–184.

46. OffieldMF, JettonTL, LaboskyPA, RayM, SteinRW, et al. (1996) PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122: 983–995.

47. XuanS, BorokMJ, DeckerKJ, BattleMA, DuncanSA, et al. (2012) Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis. J Clin Invest 122: 3516–3528.

48. TutejaG, JensenST, WhiteP, KaestnerKH (2008) Cis-regulatory modules in the mammalian liver: composition depends on strength of Foxa2 consensus site. Nucleic Acids Res 36: 4149–4157.