Skip to main content
SpringerLink
Log in

Pancreatic Development

  • Chapter
  • First Online:
Book cover Pancreatic Stem Cells

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

Abstract

Pancreatic development is arguably the best-studied example of organogenesis. Both gain-of-function and loss-of-function studies conducted in mice over the last decade have contributed to our understanding of a basic “genetic roadmap” of pancreatic – and particularly endocrine – development. Here we review this knowledge from the onset of the pancreatic program in the foregut epithelium (with the expression of the critical regulators Pdx1 and Ptf1a) to the specification of ductal, exocrine, and endocrine cell types. A special emphasis is placed on the development of endocrine beta cells, which are destroyed in type I diabetes and therefore constitute the endpoint of many stem cell differentiation protocols.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Heimberg, H., Bouwens, L., Heremans, Y., Van De Casteele, M., Lefebvre, V. & Pipeleers, D. Adult human pancreatic duct and islet cells exhibit similarities in expression and differences in phosphorylation and complex formation of the homeodomain protein Ipf-1. Diabetes. 49, 571–9 (2000).

    Article  PubMed  CAS  Google Scholar 

  2. Edlund, H. Pancreatic organogenesis - developmental mechanisms and implications for therapy. Nat Rev Genet. 3, 524–32 (2002).

    Article  PubMed  CAS  Google Scholar 

  3. Edlund, H. Developmental biology of the pancreas. Diabetes. 50(Suppl 1), S5–9 (2001).

    Article  PubMed  CAS  Google Scholar 

  4. Kumar, M. & Melton, D. Pancreas specification: a budding question. Curr Opin Genet Dev. 13, 401–7 (2003).

    Article  PubMed  CAS  Google Scholar 

  5. Kubo, A., Shinozaki, K., Shannon, J.M., Kouskoff, V., Kennedy, M., Woo, S., Fehling, H.J. & Keller, G. Development of definitive endoderm from embryonic stem cells in culture. Development. 131, 1651–62 (2004).

    Article  PubMed  CAS  Google Scholar 

  6. Tam, P.P., Kanai-Azuma, M. & Kanai, Y. Early endoderm development in vertebrates: lineage differentiation and morphogenetic function. Curr Opin Genet Dev. 13, 393–400 (2003).

    Article  PubMed  CAS  Google Scholar 

  7. Yasunaga, M., Tada, S., Torikai-Nishikawa, S., Nakano, Y., Okada, M., Jakt, L.M., Nishikawa, S., Chiba, T., Era, T. & Nishikawa, S. Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nat Biotechnol. 23, 1542–50 (2005).

    Article  PubMed  CAS  Google Scholar 

  8. Lowe, L.A., Yamada, S. & Kuehn, M.R. Genetic dissection of nodal function in patterning the mouse embryo. Development. 128, 1831–43 (2001).

    PubMed  CAS  Google Scholar 

  9. Iratni, R., Yan, Y.T., Chen, C., Ding, J., Zhang, Y., Price, S.M., Reinberg, D. & Shen, M.M. Inhibition of excess nodal signaling during mouse gastrulation by the transcriptional corepressor DRAP1. Science. 298, 1996–9 (2002).

    Article  PubMed  CAS  Google Scholar 

  10. Norris, D.P., Brennan, J., Bikoff, E.K. & Robertson, E.J. The Foxh1-dependent autoregulatory enhancer controls the level of Nodal signals in the mouse embryo. Development. 129, 3455–68 (2002).

    PubMed  CAS  Google Scholar 

  11. de Santa Barbara, P., van den Brink, G.R. & Roberts, D.J. Development and differentiation of the intestinal epithelium. Cell Mol Life Sci. 60, 1322–32 (2003).

    Article  PubMed  CAS  Google Scholar 

  12. Kanai-Azuma, M., Kanai, Y., Gad, J.M., Tajima, Y., Taya, C., Kurohmaru, M., Sanai, Y., Yonekawa, H., Yazaki, K., Tam, P.P. & Hayashi, Y. Depletion of definitive gut endoderm in Sox17-null mutant mice. Development. 129, 2367–79 (2002).

    PubMed  CAS  Google Scholar 

  13. Hudson, C., Clements, D., Friday, R.V., Stott, D. & Woodland, H.R. Xsox17alpha and -beta mediate endoderm formation in Xenopus. Cell. 91, 397–405 (1997).

    Article  PubMed  CAS  Google Scholar 

  14. Roberts, D.J., Johnson, R.L., Burke, A.C., Nelson, C.E., Morgan, B.A. & Tabin, C. Sonic hedgehog is an endodermal signal inducing Bmp-4 and Hox genes during induction and regionalization of the chick hindgut. Development. 121, 3163–74 (1995).

    PubMed  CAS  Google Scholar 

  15. Roberts, D.J., Smith, D.M., Goff, D.J. & Tabin, C.J. Epithelial-mesenchymal signaling during the regionalization of the chick gut. Development. 125, 2791–801 (1998).

    PubMed  CAS  Google Scholar 

  16. Kim, S.K. & Melton, D.A. Pancreas development is promoted by cyclopamine, a hedgehog signaling inhibitor. Proc Natl Acad Sci USA. 95, 13036–41 (1998).

    Article  PubMed  CAS  Google Scholar 

  17. Apelqvist, A., Ahlgren, U. & Edlund, H. Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. Curr Biol. 7, 801–4 (1997).

    Article  PubMed  CAS  Google Scholar 

  18. Ohlsson, H., Karlsson, K. & Edlund, T. IPF1, a homeodomain-containing transactivator of the insulin gene. EMBO J. 12, 4251–9 (1993).

    PubMed  CAS  Google Scholar 

  19. Jonsson, J., Ahlgren, U., Edlund, T. & Edlund, H. IPF1, a homeodomain protein with a dual function in pancreas development. Int J Dev Biol. 39, 789–98 (1995).

    PubMed  CAS  Google Scholar 

  20. Jonsson, J., Carlsson, L., Edlund, T. & Edlund, H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature. 371, 606–9 (1994).

    Article  PubMed  CAS  Google Scholar 

  21. Stoffers, D.A., Zinkin, N.T., Stanojevic, V., Clarke, W.L. & Habener, J.F. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet. 15, 106–10 (1997).

    Article  PubMed  CAS  Google Scholar 

  22. Ahlgren, U., Jonsson, J. & Edlund, H. The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice. Development. 122, 1409–16 (1996).

    PubMed  CAS  Google Scholar 

  23. Ahlgren, U., Jonsson, J., Jonsson, L., Simu, K. & Edlund, H. Beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev. 12, 1763–8 (1998).

    Article  PubMed  CAS  Google Scholar 

  24. Li, Y., Cao, X., Li, L.X., Brubaker, P.L., Edlund, H. & Drucker, D.J. Beta-Cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1. Diabetes. 54, 482–91 (2005).

    Article  PubMed  CAS  Google Scholar 

  25. Johnson, J.D., Ahmed, N.T., Luciani, D.S., Han, Z., Tran, H., Fujita, J., Misler, S., Edlund, H. & Polonsky, K.S. Increased islet apoptosis in Pdx1+/− mice. J Clin Invest. 111, 1147–60 (2003).

    PubMed  CAS  Google Scholar 

  26. Leibowitz, G., Ferber, S., Apelqvist, A., Edlund, H., Gross, D.J., Cerasi, E., Melloul, D. & Kaiser, N. IPF1/PDX1 deficiency and beta-cell dysfunction in Psammomys obesus, an animal with type 2 diabetes. Diabetes. 50, 1799–806 (2001).

    Article  PubMed  CAS  Google Scholar 

  27. Wessells, N.K., and Cohen, J. H. Early pancreas organogenesis: morphogenesis, tissue interactions and mass effects. Dev Biol. 15, 237 (1967).

    Article  Google Scholar 

  28. Lammert, E., Cleaver, O. & Melton, D. Induction of pancreatic differentiation by signals from blood vessels. Science. 294, 564–7 (2001).

    Article  PubMed  CAS  Google Scholar 

  29. Lammert, E., Cleaver, O. & Melton, D. Role of endothelial cells in early pancreas and liver development. Mech Dev. 120, 59–64 (2003).

    Article  PubMed  CAS  Google Scholar 

  30. Cockell, M., Stevenson, B.J., Strubin, M., Hagenbuchle, O. & Wellauer, P.K. Identification of a cell-specific DNA-binding activity that interacts with a transcriptional activator of genes expressed in the acinar pancreas. Mol Cell Biol. 9, 2464–76 (1989).

    PubMed  CAS  Google Scholar 

  31. Krapp, A., Knofler, M., Ledermann, B., Burki, K., Berney, C., Zoerkler, N., Hagenbuchle, O. & Wellauer, P.K. The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes Dev. 12, 3752–63 (1998).

    Article  PubMed  CAS  Google Scholar 

  32. Kawaguchi, Y., Cooper, B., Gannon, M., Ray, M., MacDonald, R.J. & Wright, C.V. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat Genet. 32, 128–34 (2002).

    Article  PubMed  CAS  Google Scholar 

  33. Yoshitomi, H. & Zaret, K.S. Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a. Development. 131, 807–17 (2004).

    Article  PubMed  CAS  Google Scholar 

  34. Afelik, S., Chen, Y. & Pieler, T. Combined ectopic expression of Pdx1 and Ptf1a/p48 results in the stable conversion of posterior endoderm into endocrine and exocrine pancreatic tissue. Genes Dev. 20, 1441–6 (2006).

    Article  PubMed  CAS  Google Scholar 

  35. Lemaigre, F.P., Durviaux, S.M., Truong, O., Lannoy, V.J., Hsuan, J.J. & Rousseau, G.G. Hepatocyte nuclear factor 6, a transcription factor that contains a novel type of homeodomain and a single cut domain. Proc Natl Acad Sci USA. 93, 9460–4 (1996).

    Article  PubMed  CAS  Google Scholar 

  36. Landry, C., Clotman, F., Hioki, T., Oda, H., Picard, J.J., Lemaigre, F.P. & Rousseau, G.G. HNF-6 is expressed in endoderm derivatives and nervous system of the mouse embryo and participates to the cross-regulatory network of liver-enriched transcription factors. Dev Biol. 192, 247–57 (1997).

    Article  PubMed  CAS  Google Scholar 

  37. Jacquemin, P., Durviaux, S.M., Jensen, J., Godfraind, C., Gradwohl, G., Guillemot, F., Madsen, O.D., Carmeliet, P., Dewerchin, M., Collen, D., Rousseau, G.G. & Lemaigre, F.P. Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn3. Mol Cell Biol. 20, 4445–54 (2000).

    Article  PubMed  CAS  Google Scholar 

  38. Dor, Y., Brown, J., Martinez, O.I. & Melton, D.A. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature. 429, 41–6 (2004).

    Article  PubMed  CAS  Google Scholar 

  39. Nir, T., Melton, D.A. & Dor, Y. Recovery from diabetes in mice by beta cell regeneration. J Clin Invest. 117, 2553–61 (2007).

    Article  PubMed  CAS  Google Scholar 

  40. Xu, X., D’Hoker, J., Stange, G., Bonne, S., De Leu, N., Xiao, X., Van de Casteele, M., Mellitzer, G., Ling, Z., Pipeleers, D., Bouwens, L., Scharfmann, R., Gradwohl, G. & Heimberg, H. Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell. 132, 197–207 (2008).

    Article  PubMed  CAS  Google Scholar 

  41. Jacquemin, P., Lemaigre, F.P. & Rousseau, G.G. The Onecut transcription factor HNF-6 (OC-1) is required for timely specification of the pancreas and acts upstream of Pdx-1 in the specification cascade. Dev Biol. 258, 105–16 (2003).

    Article  PubMed  CAS  Google Scholar 

  42. Barbacci, E., Chalkiadaki, A., Masdeu, C., Haumaitre, C., Lokmane, L., Loirat, C., Cloarec, S., Talianidis, I., Bellanne-Chantelot, C. & Cereghini, S. HNF1beta/TCF2 mutations impair transactivation potential through altered co-regulator recruitment. Hum Mol Genet. 13, 3139–49 (2004).

    Article  PubMed  CAS  Google Scholar 

  43. Barbacci, E., Reber, M., Ott, M.O., Breillat, C., Huetz, F. & Cereghini, S. Variant hepatocyte nuclear factor 1 is required for visceral endoderm specification. Development. 126, 4795–805 (1999).

    PubMed  CAS  Google Scholar 

  44. Haumaitre, C., Barbacci, E., Jenny, M., Ott, M.O., Gradwohl, G. & Cereghini, S. Lack of TCF2/vHNF1 in mice leads to pancreas agenesis. Proc Natl Acad Sci USA. 102, 1490–5 (2005).

    Article  PubMed  CAS  Google Scholar 

  45. Maestro, M.A., Boj, S.F., Luco, R.F., Pierreux, C.E., Cabedo, J., Servitja, J.M., German, M.S., Rousseau, G.G., Lemaigre, F.P. & Ferrer, J. Hnf6 and Tcf2 (MODY5) are linked in a gene network operating in a precursor cell domain of the embryonic pancreas. Hum Mol Genet. 12, 3307–14 (2003).

    Article  PubMed  CAS  Google Scholar 

  46. Harrison, K.A., Druey, K.M., Deguchi, Y., Tuscano, J.M. & Kehrl, J.H. A novel human homeobox gene distantly related to proboscipedia is expressed in lymphoid and pancreatic tissues. J Biol Chem. 269, 19968–75 (1994).

    PubMed  CAS  Google Scholar 

  47. Li, H., Arber, S., Jessell, T.M. & Edlund, H. Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlxb9. Nat Genet. 23, 67–70 (1999).

    PubMed  CAS  Google Scholar 

  48. Harrison, K.A., Thaler, J., Pfaff, S.L., Gu, H. & Kehrl, J.H. Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice. Nat Genet. 23, 71–5 (1999).

    PubMed  CAS  Google Scholar 

  49. Li, H. & Edlund, H. Persistent expression of Hlxb9 in the pancreatic epithelium impairs pancreatic development. Dev Biol. 240, 247–53 (2001).

    Article  PubMed  CAS  Google Scholar 

  50. Brocard, J., Feil, R., Chambon, P. & Metzger, D. A chimeric Cre recombinase inducible by synthetic, but not by natural ligands of the glucocorticoid receptor. Nucleic Acids Res. 26, 4086–90 (1998).

    Article  PubMed  CAS  Google Scholar 

  51. Feil, R., Brocard, J., Mascrez, B., LeMeur, M., Metzger, D. & Chambon, P. Ligand-activated site-specific recombination in mice. Proc Natl Acad Sci USA. 93, 10887–90 (1996).

    Article  PubMed  CAS  Google Scholar 

  52. Gu, G., Dubauskaite, J. & Melton, D.A. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development. 129, 2447–57 (2002).

    PubMed  CAS  Google Scholar 

  53. Gu, G., Brown, J.R. & Melton, D.A. Direct lineage tracing reveals the ontogeny of pancreatic cell fates during mouse embryogenesis. Mech Dev. 120, 35–43 (2003).

    Article  PubMed  CAS  Google Scholar 

  54. Danielian, P.S., Muccino, D., Rowitch, D.H., Michael, S.K. & McMahon, A.P. Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Curr Biol. 8, 1323–6 (1998).

    Article  PubMed  CAS  Google Scholar 

  55. Chitnis, A.B. The role of Notch in lateral inhibition and cell fate specification. Mol Cell Neurosci. 6, 311–21 (1995).

    Article  CAS  Google Scholar 

  56. Apelqvist, A., Li, H., Sommer, L., Beatus, P., Anderson, D.J., Honjo, T., Hrabe de Angelis, M., Lendahl, U. & Edlund, H. Notch signalling controls pancreatic cell differentiation. Nature. 400, 877–81 (1999).

    Article  PubMed  CAS  Google Scholar 

  57. Gradwohl, G., Dierich, A., LeMeur, M. & Guillemot, F. Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci USA. 97, 1607–11 (2000).

    Article  PubMed  CAS  Google Scholar 

  58. Jensen, J., Pedersen, E.E., Galante, P., Hald, J., Heller, R.S., Ishibashi, M., Kageyama, R., Guillemot, F., Serup, P. & Madsen, O.D. Control of endodermal endocrine development by Hes-1. Nat Genet. 24, 36–44 (2000).

    Article  PubMed  CAS  Google Scholar 

  59. Edlund, H. Factors controlling pancreatic cell differentiation and function. Diabetologia. 44, 1071–9 (2001).

    Article  PubMed  CAS  Google Scholar 

  60. Grapin-Botton, A., Majithia, A.R. & Melton, D.A. Key events of pancreas formation are triggered in gut endoderm by ectopic expression of pancreatic regulatory genes. Genes Dev. 15, 444–54 (2001).

    Article  PubMed  CAS  Google Scholar 

  61. Domínguez-Bendala, J., Klein, D., Ribeiro, M., Ricordi, C., Inverardi, L., Pastori, R. & Edlund, H. TAT-mediated neurogenin 3 protein transduction stimulates pancreatic endocrine differentiation in vitro. Diabetes. 54, 720–6 (2005).

    Article  PubMed  Google Scholar 

  62. Dawid, I.B., Toyama, R. & Taira, M. LIM domain proteins. C R Acad Sci III. 318, 295–306 (1995).

    PubMed  CAS  Google Scholar 

  63. Karlsson, O., Thor, S., Norberg, T., Ohlsson, H. & Edlund, T. Insulin gene enhancer binding protein Isl-1 is a member of a novel class of proteins containing both a homeo- and a Cys-His domain. Nature. 344, 879–82 (1990).

    Article  PubMed  CAS  Google Scholar 

  64. Ahlgren, U., Pfaff, S.L., Jessell, T.M., Edlund, T. & Edlund, H. Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells. Nature. 385, 257–60 (1997).

    Article  PubMed  CAS  Google Scholar 

  65. Hussain, M.A., Lee, J., Miller, C.P. & Habener, J.F. POU domain transcription factor brain 4 confers pancreatic alpha-cell-specific expression of the proglucagon gene through interaction with a novel proximal promoter G1 element. Mol Cell Biol. 17, 7186–94 (1997).

    PubMed  CAS  Google Scholar 

  66. Heller, R.S., Stoffers, D.A., Liu, A., Schedl, A., Crenshaw, E.B., III, Madsen, O.D. & Serup, P. The role of Brn4/Pou3f4 and Pax6 in forming the pancreatic glucagon cell identity. Dev Biol. 268, 123–34 (2004).

    Article  PubMed  CAS  Google Scholar 

  67. Hussain, M.A., Miller, C.P. & Habener, J.F. Brn-4 transcription factor expression targeted to the early developing mouse pancreas induces ectopic glucagon gene expression in insulin-producing beta cells. J Biol Chem. 277, 16028–32 (2002).

    Article  PubMed  CAS  Google Scholar 

  68. Naya, F.J., Stellrecht, C.M. & Tsai, M.J. Tissue-specific regulation of the insulin gene by a novel basic helix-loop-helix transcription factor. Genes Dev. 9, 1009–19 (1995).

    Article  PubMed  CAS  Google Scholar 

  69. Naya, F.J., Huang, H.P., Qiu, Y., Mutoh, H., DeMayo, F.J., Leiter, A.B. & Tsai, M.J. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev. 11, 2323–34 (1997).

    Article  PubMed  CAS  Google Scholar 

  70. Huang, H.P., Liu, M., El-Hodiri, H.M., Chu, K., Jamrich, M. & Tsai, M.J. Regulation of the pancreatic islet-specific gene BETA2 (neuroD) by neurogenin 3. Mol Cell Biol. 20, 3292–307 (2000).

    Article  PubMed  CAS  Google Scholar 

  71. Sander, M., Sussel, L., Conners, J., Scheel, D., Kalamaras, J., Dela Cruz, F., Schwitzgebel, V., Hayes-Jordan, A. & German, M. Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas. Development. 127, 5533–40 (2000).

    PubMed  CAS  Google Scholar 

  72. Sussel, L., Kalamaras, J., Hartigan-O’Connor, D.J., Meneses, J.J., Pedersen, R.A., Rubenstein, J.L. & German, M.S. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development. 125, 2213–21 (1998).

    PubMed  CAS  Google Scholar 

  73. Nishimura, W., Kondo, T., Salameh, T., El Khattabi, I., Dodge, R., Bonner-Weir, S. & Sharma, A. A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells. Dev Biol. 293, 526–39 (2006).

    Article  PubMed  CAS  Google Scholar 

  74. Sosa-Pineda, B., Chowdhury, K., Torres, M., Oliver, G. & Gruss, P. The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature. 386, 399–402 (1997).

    Article  PubMed  CAS  Google Scholar 

  75. Sosa-Pineda, B. The gene Pax4 is an essential regulator of pancreatic beta-cell development. Mol Cells. 18, 289–94 (2004).

    PubMed  CAS  Google Scholar 

  76. Wang, J., Elghazi, L., Parker, S.E., Kizilocak, H., Asano, M., Sussel, L. & Sosa-Pineda, B. The concerted activities of Pax4 and Nkx2.2 are essential to initiate pancreatic beta-cell differentiation. Dev Biol. 266, 178–89 (2004).

    Article  PubMed  CAS  Google Scholar 

  77. Heremans, Y., Van De Casteele, M., in’t Veld, P., Gradwohl, G., Serup, P., Madsen, O., Pipeleers, D. & Heimberg, H. Recapitulation of embryonic neuroendocrine differentiation in adult human pancreatic duct cells expressing neurogenin 3. J Cell Biol. 159, 303–12 (2002).

    Article  PubMed  CAS  Google Scholar 

  78. Smith, S.B., Gasa, R., Watada, H., Wang, J., Griffen, S.C. & German, M.S. Neurogenin3 and hepatic nuclear factor 1 cooperate in activating pancreatic expression of Pax4. J Biol Chem. 278, 38254–9 (2003).

    Article  PubMed  CAS  Google Scholar 

  79. Blyszczuk, P., Czyz, J., Kania, G., Wagner, M., Roll, U., St-Onge, L. & Wobus, A.M. Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells. Proc Natl Acad Sci USA. 100, 998–1003 (2003).

    Article  PubMed  CAS  Google Scholar 

  80. Collombat, P., Hecksher-Sorensen, J., Broccoli, V., Krull, J., Ponte, I., Mundiger, T., Smith, J., Gruss, P., Serup, P. & Mansouri, A. 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, 2969–80 (2005).

    Article  PubMed  CAS  Google Scholar 

  81. Collombat, P., Mansouri, A., Hecksher-Sorensen, J., Serup, P., Krull, J., Gradwohl, G. & Gruss, P. Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes Dev. 17, 2591–603 (2003).

    Article  PubMed  CAS  Google Scholar 

  82. Heller, R.S., Jenny, M., Collombat, P., Mansouri, A., Tomasetto, C., Madsen, O.D., Mellitzer, G., Gradwohl, G. & Serup, P. Genetic determinants of pancreatic epsilon-cell development. Dev Biol. 286, 217–24 (2005).

    Article  PubMed  CAS  Google Scholar 

  83. Price, M. Members of the Dlx- and Nkx2-gene families are regionally expressed in the developing forebrain. J Neurobiol. 24, 1385–99 (1993).

    Article  PubMed  CAS  Google Scholar 

  84. Rudnick, A., Ling, T.Y., Odagiri, H., Rutter, W.J. & German, M.S. Pancreatic beta cells express a diverse set of homeobox genes. Proc Natl Acad Sci USA. 91, 12203–7 (1994).

    Article  PubMed  CAS  Google Scholar 

  85. Dohrmann, C., Gruss, P. & Lemaire, L. Pax genes and the differentiation of hormone-producing endocrine cells in the pancreas. Mech Dev. 92, 47–54 (2000).

    Article  PubMed  CAS  Google Scholar 

  86. Cvekl, A., Kashanchi, F., Sax, C.M., Brady, J.N. & Piatigorsky, J. Transcriptional regulation of the mouse alpha A-crystallin gene: activation dependent on a cyclic AMP-responsive element (DE1/CRE) and a Pax-6-binding site. Mol Cell Biol. 15, 653–60 (1995).

    PubMed  CAS  Google Scholar 

  87. Hill, R.E., Favor, J., Hogan, B.L., Ton, C.C., Saunders, G.F., Hanson, I.M., Prosser, J., Jordan, T., Hastie, N.D. & van Heyningen, V. Mouse small eye results from mutations in a paired-like homeobox-containing gene. Nature. 354, 522–5 (1991).

    Article  PubMed  CAS  Google Scholar 

  88. Turque, N., Plaza, S., Radvanyi, F., Carriere, C. & Saule, S. Pax-QNR/Pax-6, a paired box- and homeobox-containing gene expressed in neurons, is also expressed in pancreatic endocrine cells. Mol Endocrinol. 8, 929–38 (1994).

    Article  PubMed  CAS  Google Scholar 

  89. St-Onge, L., Sosa-Pineda, B., Chowdhury, K., Mansouri, A. & Gruss, P. Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas. Nature. 387, 406–9 (1997).

    Article  PubMed  CAS  Google Scholar 

  90. Sander, M., Neubuser, A., Kalamaras, J., Ee, H.C., Martin, G.R. & German, M.S. Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development. Genes Dev. 11, 1662–73 (1997).

    Article  PubMed  CAS  Google Scholar 

  91. Miura, H., Yanazawa, M., Kato, K. & Kitamura, K. Expression of a novel aristaless related homeobox gene ‘Arx’ in the vertebrate telencephalon, diencephalon and floor plate. Mech Dev. 65, 99–109 (1997).

    Article  PubMed  CAS  Google Scholar 

  92. Kawauchi, S., Takahashi, S., Nakajima, O., Ogino, H., Morita, M., Nishizawa, M., Yasuda, K. & Yamamoto, M. Regulation of lens fiber cell differentiation by transcription factor c-Maf. J Biol Chem. 274, 19254–60 (1999).

    Article  PubMed  CAS  Google Scholar 

  93. Ochi, H., Sakagami, K., Ishii, A., Morita, N., Nishiuchi, M., Ogino, H. & Yasuda, K. Temporal expression of L-Maf and RaxL in developing chicken retina are arranged into mosaic pattern. Gene Expr Patterns. 4, 489–94 (2004).

    Article  PubMed  CAS  Google Scholar 

  94. Ogino, H. & Yasuda, K. Induction of lens differentiation by activation of a bZIP transcription factor, L-Maf. Science. 280, 115–8 (1998).

    Article  PubMed  CAS  Google Scholar 

  95. Reza, H.M., Ogino, H. & Yasuda, K. L-Maf, a downstream target of Pax6, is essential for chick lens development. Mech Dev. 116, 61–73 (2002).

    Article  PubMed  CAS  Google Scholar 

  96. Zhang, C., Moriguchi, T., Kajihara, M., Esaki, R., Harada, A., Shimohata, H., Oishi, H., Hamada, M., Morito, N., Hasegawa, K., Kudo, T., Engel, J.D., Yamamoto, M. & Takahashi, S. MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol. 25, 4969–76 (2005).

    Article  PubMed  CAS  Google Scholar 

  97. Artner, I., Blanchi, B., Raum, J.C., Guo, M., Kaneko, T., Cordes, S., Sieweke, M. & Stein, R. MafB is required for islet beta cell maturation. Proc Natl Acad Sci USA. 104, 3853–8 (2007).

    Article  PubMed  CAS  Google Scholar 

  98. Ang, S.L. & Rossant, J. HNF-3 beta is essential for node and notochord formation in mouse development. Cell. 78, 561–74 (1994).

    Article  PubMed  CAS  Google Scholar 

  99. Weinstein, D.C., Ruiz i Altaba, A., Chen, W.S., Hoodless, P., Prezioso, V.R., Jessell, T.M. & Darnell, J.E., Jr. The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo. Cell. 78, 575–88 (1994).

    Article  PubMed  CAS  Google Scholar 

  100. Sund, N.J., Vatamaniuk, M.Z., Casey, M., Ang, S.L., Magnuson, M.A., Stoffers, D.A., Matschinsky, F.M. & Kaestner, K.H. Tissue-specific deletion of Foxa2 in pancreatic beta cells results in hyperinsulinemic hypoglycemia. Genes Dev. 15, 1706–15 (2001).

    Article  PubMed  CAS  Google Scholar 

  101. Ben-Shushan, E., Marshak, S., Shoshkes, M., Cerasi, E. & Melloul, D. A pancreatic beta -cell-specific enhancer in the human PDX-1 gene is regulated by hepatocyte nuclear factor 3beta (HNF-3beta), HNF-1alpha, and SPs transcription factors. J Biol Chem. 276, 17533–40 (2001).

    Article  PubMed  CAS  Google Scholar 

  102. Lee, C.S., Sund, N.J., Behr, R., Herrera, P.L. & Kaestner, K.H. Foxa2 is required for the differentiation of pancreatic alpha-cells. Dev Biol. 278, 484–95 (2005).

    Article  PubMed  CAS  Google Scholar 

  103. Pictet, R., Rutter, W. J. Development of the embryonic endocrine pancreas. In Handbook of Physiology, 25–66 (Williams & Wilkins, Baltimore, 1972).

    Google Scholar 

  104. Pictet, R.L., Clark, W.R., Williams, R.H. & Rutter, W.J. An ultrastructural analysis of the developing embryonic pancreas. Dev Biol. 29, 436–67 (1972).

    Article  PubMed  CAS  Google Scholar 

  105. Tulachan, S.S., Tei, E., Hembree, M., Crisera, C., Prasadan, K., Koizumi, M., Shah, S., Guo, P., Bottinger, E. & Gittes, G.K. TGF-beta isoform signaling regulates secondary transition and mesenchymal-induced endocrine development in the embryonic mouse pancreas. Dev Biol. 305, 508–21 (2007).

    Article  PubMed  CAS  Google Scholar 

  106. Lynn, F.C., Smith, S.B., Wilson, M.E., Yang, K.Y., Nekrep, N. & German, M.S. Sox9 coordinates a transcriptional network in pancreatic progenitor cells. Proc Natl Acad Sci USA. 104, 10500–5 (2007).

    Article  PubMed  CAS  Google Scholar 

  107. Oliver, G., Sosa-Pineda, B., Geisendorf, S., Spana, E.P., Doe, C.Q. & Gruss, P. Prox 1, a prospero-related homeobox gene expressed during mouse development. Mech Dev. 44, 3–16 (1993).

    Article  PubMed  CAS  Google Scholar 

  108. Burke, Z. & Oliver, G. Prox1 is an early specific marker for the developing liver and pancreas in the mammalian foregut endoderm. Mech Dev. 118, 147–55 (2002).

    Article  PubMed  CAS  Google Scholar 

  109. Wang, J., Kilic, G., Aydin, M., Burke, Z., Oliver, G. & Sosa-Pineda, B. Prox1 activity controls pancreas morphogenesis and participates in the production of “secondary transition” pancreatic endocrine cells. Dev Biol. 286, 182–94 (2005).

    Article  PubMed  CAS  Google Scholar 

  110. Wilson, M.E., Yang, K.Y., Kalousova, A., Lau, J., Kosaka, Y., Lynn, F.C., Wang, J., Mrejen, C., Episkopou, V., Clevers, H.C. & German, M.S. The HMG box transcription factor Sox4 contributes to the development of the endocrine pancreas. Diabetes. 54, 3402–9 (2005).

    Article  PubMed  CAS  Google Scholar 

  111. Ya, J., Schilham, M.W., de Boer, P.A., Moorman, A.F., Clevers, H. & Lamers, W.H. Sox4-deficiency syndrome in mice is an animal model for common trunk. Circ Res. 83, 986–94 (1998).

    PubMed  CAS  Google Scholar 

  112. Nelson, C.M., Jean, R.P., Tan, J.L., Liu, W.F., Sniadecki, N.J., Spector, A.A. & Chen, C.S. Emergent patterns of growth controlled by multicellular form and mechanics. Proc Natl Acad Sci USA. 102, 11594–9 (2005).

    Article  PubMed  CAS  Google Scholar 

  113. Chen, C. Using microenvironment to engineer stem cell function. Conf Proc IEEE Eng Med Biol Soc. 7, 4964 (2004).

    PubMed  Google Scholar 

  114. Liu, H., Lin, J. & Roy, K. Effect of 3D scaffold and dynamic culture condition on the global gene expression profile of mouse embryonic stem cells. Biomaterials. 27, 5978–89 (2006).

    Article  PubMed  CAS  Google Scholar 

  115. Harrington, D.B. & Becker, R.O. Electrical stimulation of RNA and protein synthesis in the frog erythrocyte. Exp Cell Res. 76, 95–8 (1973).

    Article  PubMed  CAS  Google Scholar 

  116. Robinson, K.R. & Messerli, M.A. Left/right, up/down: the role of endogenous electrical fields as directional signals in development, repair and invasion. Bioessays. 25, 759–66 (2003).

    Article  PubMed  Google Scholar 

  117. Levin, M. Bioelectromagnetics in morphogenesis. Bioelectromagnetics. 24, 295–315 (2003).

    Article  PubMed  CAS  Google Scholar 

  118. Shi, R. & Borgens, R.B. Three-dimensional gradients of voltage during development of the nervous system as invisible coordinates for the establishment of embryonic pattern. Dev Dyn. 202, 101–14 (1995).

    Article  PubMed  CAS  Google Scholar 

  119. Hotary, K.B. & Robinson, K.R. Endogenous electrical currents and voltage gradients in Xenopus embryos and the consequences of their disruption. Dev Biol. 166, 789–800 (1994).

    Article  PubMed  CAS  Google Scholar 

  120. Borgens, R.B., Callahan, L. & Rouleau, M.F. Anatomy of axolotl flank integument during limb bud development with special reference to a transcutaneous current predicting limb formation. J Exp Zool. 244, 203–14 (1987).

    Article  PubMed  CAS  Google Scholar 

  121. Borgens, R.B., Rouleau, M.F. & DeLanney, L.E. A steady efflux of ionic current predicts hind limb development in the axolotl. J Exp Zool. 228, 491–503 (1983).

    Article  PubMed  CAS  Google Scholar 

  122. Simon, M.C. & Keith, B. The role of oxygen availability in embryonic development and stem cell function. Nat Rev Mol Cell Biol. 9, 285–96 (2008).

    Article  PubMed  CAS  Google Scholar 

  123. Csete, M. Oxygen in the cultivation of stem cells. Ann NY Acad Sci. 1049, 1–8 (2005).

    Article  PubMed  CAS  Google Scholar 

  124. Fraker, C.A., Alvarez, S., Papadopoulos, P., Giraldo, J., Gu, W., Ricordi, C., Inverardi, L. & Dominguez-Bendala, J. Enhanced oxygenation promotes beta-cell differentiation in vitro. Stem Cells. 25, 3155–64 (2007).

    Article  PubMed  CAS  Google Scholar 

  125. Fraker, C., Ricordi, C., Inverardi, L., and Dominguez-Bendala, J. Oxygen: a master regulator of pancreatic development? Biol Cell. (in press). (2009).

    Google Scholar 

  126. Pugh, C.W. & Ratcliffe, P.J. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 9, 677–84 (2003).

    Article  PubMed  CAS  Google Scholar 

  127. Bell, E.L., Emerling, B.M. & Chandel, N.S. Mitochondrial regulation of oxygen sensing. Mitochondrion. 5, 322–32 (2005).

    Article  PubMed  CAS  Google Scholar 

  128. Diez, H., Fischer, A., Winkler, A., Hu, C.J., Hatzopoulos, A.K., Breier, G. & Gessler, M. Hypoxia-mediated activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate. Exp Cell Res. 313, 1–9 (2007).

    Article  PubMed  CAS  Google Scholar 

  129. Moritz, W., Meier, F., Stroka, D.M., Giuliani, M., Kugelmeier, P., Nett, P.C., Lehmann, R., Candinas, D., Gassmann, M. & Weber, M. Apoptosis in hypoxic human pancreatic islets correlates with HIF-1alpha expression. FASEB J. 16, 745–7 (2002).

    PubMed  CAS  Google Scholar 

  130. Gustafsson, M.V., Zheng, X., Pereira, T., Gradin, K., Jin, S., Lundkvist, J., Ruas, J.L., Poellinger, L., Lendahl, U. & Bondesson, M. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell. 9, 617–28 (2005).

    Article  PubMed  CAS  Google Scholar 

  131. Ezashi, T., Das, P. & Roberts, R.M. Low O2 tensions and the prevention of differentiation of hES cells. Proc Natl Acad Sci USA. 102, 4783–8 (2005).

    Article  PubMed  CAS  Google Scholar 

  132. Mitchell, J.A. & Yochim, J.M. Intrauterine oxygen tension during the estrous cycle in the rat: its relation to uterine respiration and vascular activity. Endocrinology. 83, 701–5 (1968).

    Article  PubMed  CAS  Google Scholar 

  133. Gassmann, M., Fandrey, J., Bichet, S., Wartenberg, M., Marti, H.H., Bauer, C., Wenger, R.H. & Acker, H. Oxygen supply and oxygen-dependent gene expression in differentiating embryonic stem cells. Proc Natl Acad Sci USA. 93, 2867–72 (1996).

    Article  PubMed  CAS  Google Scholar 

  134. Colen, K.L., Crisera, C.A., Rose, M.I., Connelly, P.R., Longaker, M.T. & Gittes, G.K. Vascular development in the mouse embryonic pancreas and lung. J Pediatr Surg. 34, 781–5 (1999).

    Article  PubMed  CAS  Google Scholar 

  135. Kadesch, T. Notch signaling: the demise of elegant simplicity. Curr Opin Genet Dev. 14, 506–12 (2004).

    Article  PubMed  CAS  Google Scholar 

  136. Hart, A., Papadopoulou, S. & Edlund, H. Fgf10 maintains notch activation, stimulates proliferation, and blocks differentiation of pancreatic epithelial cells. Dev Dyn. 228, 185–93 (2003).

    Article  PubMed  CAS  Google Scholar 

  137. Murtaugh, L.C., Stanger, B.Z., Kwan, K.M. & Melton, D.A. Notch signaling controls multiple steps of pancreatic differentiation. Proc Natl Acad Sci USA. 100, 14920–5 (2003).

    Article  PubMed  CAS  Google Scholar 

  138. Cejudo-Martin, P. & Johnson, R.S. A new notch in the HIF belt: how hypoxia impacts differentiation. Dev Cell. 9, 575–6 (2005).

    Article  PubMed  CAS  Google Scholar 

  139. Sainson, R.C. & Harris, A.L. Hypoxia-regulated differentiation: let’s step it up a Notch. Trends Mol Med. 12, 141–3 (2006).

    Article  PubMed  CAS  Google Scholar 

  140. Wells, J.M., Esni, F., Boivin, G.P., Aronow, B.J., Stuart, W., Combs, C., Sklenka, A., Leach, S.D. & Lowy, A.M. Wnt/beta-catenin signaling is required for development of the exocrine pancreas. BMC Dev Biol. 7, 4 (2007).

    Article  PubMed  CAS  Google Scholar 

  141. Murtaugh, L.C., Law, A.C., Dor, Y. & Melton, D.A. Beta-catenin is essential for pancreatic acinar but not islet development. Development. 132, 4663–74 (2005).

    Article  PubMed  CAS  Google Scholar 

  142. Kaidi, A., Williams, A.C. & Paraskeva, C. Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat Cell Biol. 9, 210–7 (2007).

    Article  PubMed  CAS  Google Scholar 

  143. Funato, Y., Michiue, T., Asashima, M. & Miki, H. The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-beta-catenin signalling through dishevelled. Nat Cell Biol. 8, 501–8 (2006).

    Article  PubMed  CAS  Google Scholar 

  144. Liu, W.D., Wang, H.W., Muguira, M., Breslin, M.B. & Lan, M.S. INSM1 functions as a transcriptional repressor of the neuroD/beta2 gene through the recruitment of cyclin D1 and histone deacetylases. Biochem J. 397, 169–77 (2006).

    Article  PubMed  CAS  Google Scholar 

  145. Haumaitre, C., Lenoir, O. & Scharfmann, R. Histone deacetylase inhibitors modify pancreatic cell fate determination and amplify endocrine progenitors. Mol Cell Biol. 28, 6373–83 (2008).

    Article  PubMed  CAS  Google Scholar 

  146. Goicoa, S., Álvarez, S., Ricordi, C., Inverardi, L. and Domínguez-Bendala, J. Sodium butyrate activates genes of early pancreatic development in ES cells. Cloning Stem Cells. 8, 140–49 (2006).

    Article  PubMed  CAS  Google Scholar 

  147. Piper, K., Brickwood, S., Turnpenny, L.W., Cameron, I.T., Ball, S.G., Wilson, D.I. & Hanley, N.A. Beta cell differentiation during early human pancreas development. J Endocrinol. 181, 11–23 (2004).

    Article  PubMed  CAS  Google Scholar 

  148. Falin, L.I. The development and cytodifferentiation of the islets of Langerhans in human embryos and foetuses. Acta Anat (Basel). 68, 147–68 (1967).

    Article  CAS  Google Scholar 

  149. Slack, J.M. Developmental biology of the pancreas. Development. 121, 1569–80 (1995).

    PubMed  CAS  Google Scholar 

  150. Bartel, D.P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 116, 281–97 (2004).

    Article  PubMed  CAS  Google Scholar 

  151. Eulalio, A., Huntzinger, E. & Izaurralde, E. Getting to the root of miRNA-mediated gene silencing. Cell. 132, 9–14 (2008).

    Article  PubMed  CAS  Google Scholar 

  152. Kim, V.N. & Nam, J.W. Genomics of microRNA. Trends Genet. 22, 165–73 (2006).

    Article  PubMed  CAS  Google Scholar 

  153. Griffiths-Jones, S. The microRNA Registry. Nucleic Acids Res. 32, D109–11 (2004).

    Article  PubMed  CAS  Google Scholar 

  154. Kuhn, D.E., Martin, M.M., Feldman, D.S., Terry, A.V., Jr., Nuovo, G.J. & Elton, T.S. Experimental validation of miRNA targets. Methods. 44, 47–54 (2008).

    Article  PubMed  CAS  Google Scholar 

  155. Poy, M.N., Eliasson, L., Krutzfeldt, J., Kuwajima, S., Ma, X., Macdonald, P.E., Pfeffer, S., Tuschl, T., Rajewsky, N., Rorsman, P. & Stoffel, M. A pancreatic islet-specific microRNA regulates insulin secretion. Nature. 432, 226–30 (2004).

    Article  PubMed  CAS  Google Scholar 

  156. Wienholds, E., Kloosterman, W.P., Miska, E., Alvarez-Saavedra, E., Berezikov, E., de Bruijn, E., Horvitz, H.R., Kauppinen, S. & Plasterk, R.H. MicroRNA expression in zebrafish embryonic development. Science. 309, 310–1 (2005).

    Article  PubMed  CAS  Google Scholar 

  157. Lagos-Quintana, M., Rauhut, R., Yalcin, A., Meyer, J., Lendeckel, W. & Tuschl, T. Identification of tissue-specific microRNAs from mouse. Curr Biol. 12, 735–9 (2002).

    Article  PubMed  CAS  Google Scholar 

  158. Lynn, F.C., Skewes-Cox, P., Kosaka, Y., McManus, M.T., Harfe, B.D. & German, M.S. MicroRNA expression is required for pancreatic islet cell genesis in the mouse. Diabetes. 56(12):2938–45 (2007).

    Article  PubMed  CAS  Google Scholar 

  159. Kloosterman, W.P., Lagendijk, A.K., Ketting, R.F., Moulton, J.D. & Plasterk, R.H. Targeted inhibition of miRNA maturation with morpholinos reveals a role for miR-375 in pancreatic islet development. PLoS Biol. 5, e203 (2007).

    Article  PubMed  CAS  Google Scholar 

  160. Bravo-Egana, V., Rosero, S., Molano, R.D., Pileggi, A., Ricordi, C., Dominguez-Bendala, J. & Pastori, R.L. Quantitative differential expression analysis reveals miR-7 as major islet microRNA. Biochem Biophys Res Commun. 366, 922–6 (2008).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Development & Stem Cell Laboratory, Diabetes Research Institute University of Miami, Miami, FL, 33136, USA

    Juan Domínguez-Bendala MSc, PhD (Research Assistant Professor of Surgery Pancreatic)

Authors
  1. Juan Domínguez-Bendala MSc, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Juan Domínguez-Bendala MSc, PhD .

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Humana Press, a part of Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Domínguez-Bendala, J. (2009). Pancreatic Development. In: Pancreatic Stem Cells. Stem Cell Biology and Regenerative Medicine. Humana Press. https://doi.org/10.1007/978-1-60761-132-5_2

Download citation

Publish with us

Policies and ethics

Search

Navigation