Table of Contents
ISRN Endocrinology
Volume 2012, Article ID 640956, 12 pages
http://dx.doi.org/10.5402/2012/640956
Review Article

Development and Regeneration in the Endocrine Pancreas

1Research Group Molecular Cell Differentiation, Department Molecular Cell Biology, Max-Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Goettingen, Germany
2Department of Clinical Neurophysiology, University of Goettingen, Robert-Koch-Strasse 40, 37075 Goettingen, Germany

Received 13 November 2012; Accepted 10 December 2012

Academic Editors: H. Galbo, R. Gasa, A. I. Torres, and A. O. L. Wong

Copyright © 2012 Ahmed Mansouri. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. P. Collombat, P. Serup, and A. Mansouri, “Specifying pancreatic endocrine cell fates,” Mechanisms of Development, vol. 123, no. 7, pp. 501–512, 2006. View at Publisher · View at Google Scholar
  2. L. C. Murtaugh, “Pancreas and beta-cell development: from the actual to the possible,” Development, vol. 134, no. 3, pp. 427–438, 2007. View at Publisher · View at Google Scholar · View at Scopus
  3. J. M. Oliver-Krasinski and D. A. Stoffers, “On the origin of the β cell,” Genes and Development, vol. 22, no. 15, pp. 1998–2021, 2008. View at Publisher · View at Google Scholar · View at Scopus
  4. F. C. Pan and C. Wright, “Pancreas organogenesis: from bud to plexus to gland,” Developmental Dynamics, vol. 240, no. 3, pp. 530–565, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. S. Rieck, E. D. Bankaitis, and C. V. E. Wright, “Lineage determinants in early endocrine development,” Seminars in Cell and Developmental Biology, vol. 23, no. 6, pp. 673–684, 2012. View at Publisher · View at Google Scholar
  6. M. A. Guney and M. Gannon, “Pancreas cell fate,” Birth Defects Research C, vol. 87, no. 3, pp. 232–248, 2009. View at Publisher · View at Google Scholar · View at Scopus
  7. G. K. Gittes, “Developmental biology of the pancreas: a comprehensive review,” Developmental Biology, vol. 326, no. 1, pp. 4–35, 2009. View at Publisher · View at Google Scholar · View at Scopus
  8. J. Jonsson, L. Carlsson, T. Edlund, and H. Edlund, “Insulin-promoter-factor 1 is required for pancreas development in mice,” Nature, vol. 371, no. 6498, pp. 606–609, 1994. View at Publisher · View at Google Scholar · View at Scopus
  9. M. F. Offield, T. L. Jetton, P. A. Labosky et al., “PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum,” Development, vol. 122, no. 3, pp. 983–995, 1996. View at Google Scholar · View at Scopus
  10. Y. Kawaguchi, B. Cooper, M. Gannon, M. Ray, R. J. MacDonald, and C. V. E. Wright, “The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors,” Nature Genetics, vol. 32, no. 1, pp. 128–134, 2002. View at Publisher · View at Google Scholar · View at Scopus
  11. G. Gu, J. R. Brown, and D. A. Melton, “Direct lineage tracing reveals the ontogeny of pancreatic cell fates during mouse embryogenesis,” Mechanisms of Development, vol. 120, no. 1, pp. 35–43, 2003. View at Publisher · View at Google Scholar · View at Scopus
  12. R. L. Pictet, W. R. Clark, R. H. Williams, and W. J. Rutter, “An ultrastructural analysis of the developing embryonic pancreas,” Developmental Biology, vol. 29, no. 4, pp. 436–467, 1972. View at Google Scholar · View at Scopus
  13. Q. Zhou, A. C. Law, J. Rajagopal, W. J. Anderson, P. A. Gray, and D. A. Melton, “A multipotent progenitor domain guides pancreatic organogenesis,” Developmental Cell, vol. 13, no. 1, pp. 103–114, 2007. View at Publisher · View at Google Scholar · View at Scopus
  14. J. P. Mordes and A. A. Rossini, “Animal models of diabetes,” American Journal of Medicine, vol. 70, no. 2, pp. 353–360, 1981. View at Google Scholar · View at Scopus
  15. L. Bouwens and G. Klöppel, “Islet cell neogenesis in the pancreas,” Virchows Archiv, vol. 427, no. 6, pp. 553–560, 1996. View at Google Scholar · View at Scopus
  16. S. Bonner-Weir and A. Sharma, “Pancreatic stem cells,” Journal of Pathology, vol. 197, pp. 519–526, 2002. View at Google Scholar
  17. T. Nir, D. A. Melton, and Y. Dor, “Recovery from diabetes in mice by β cell regeneration,” Journal of Clinical Investigation, vol. 117, no. 9, pp. 2553–2561, 2007. View at Publisher · View at Google Scholar · View at Scopus
  18. H. Liu, Y. Guz, M. H. Kedees, J. Winkler, and G. Teitelman, “Precursor cells in mouse islets generate new β-cells in vivo during aging and after islet injury,” Endocrinology, vol. 151, no. 2, pp. 520–528, 2010. View at Publisher · View at Google Scholar · View at Scopus
  19. Y. Guz, I. Nasir, and G. Teitelman, “Regeneration of pancreatic β cells from intra-islet precursor cells in an experimental model of diabetes,” Endocrinology, vol. 142, no. 11, pp. 4956–4968, 2001. View at Publisher · View at Google Scholar · View at Scopus
  20. F. Thorel, V. Népote, I. Avril et al., “Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss,” Nature, vol. 464, no. 7292, pp. 1149–1154, 2010. View at Publisher · View at Google Scholar · View at Scopus
  21. A. Lechner and J. F. Habener, “Stem/progenitor cells derived from adult tissues: potential for the treatment of diabetes mellitus,” American Journal of Physiology, vol. 284, no. 2, pp. E259–E266, 2003. View at Google Scholar · View at Scopus
  22. P. Collombat, X. Xu, H. Heimberg, and A. Mansouri, “Pancreatic beta-cells: from generation to regeneration,” Seminars in Cell and Developmental Biology, vol. 21, no. 8, pp. 838–844, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. Y. Dor, J. Brown, O. I. Martinez, and D. A. Melton, “Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation,” Nature, vol. 429, no. 6987, pp. 41–46, 2004. View at Publisher · View at Google Scholar · View at Scopus
  24. K. Brennand, D. Huangfu, and D. Melton, “All beta cells contribute equally to islet growth and maintenance,” PLoS biology, vol. 5, no. 7, p. e163, 2007. View at Publisher · View at Google Scholar · View at Scopus
  25. M. Teta, M. M. Rankin, S. Y. Long, G. M. Stein, and J. A. Kushner, “Growth and regeneration of adult beta cells does not involve specialized progenitors,” Developmental Cell, vol. 12, no. 5, pp. 817–826, 2007. View at Publisher · View at Google Scholar · View at Scopus
  26. A. Fernandes, L. C. King, Y. Guz, R. Stein, C. V. E. Wright, and G. Teitelman, “Differentiation of new insulin-producing cells is induced by injury in adult pancreatic islets,” Endocrinology, vol. 138, no. 4, pp. 1750–1762, 1997. View at Publisher · View at Google Scholar · View at Scopus
  27. R. De Haro-Hernández, L. Cabrera-Muñoz, and J. D. Méndez, “Regeneration of β-cells and neogenesis from small ducts or acinar cells promote recovery of endocrine pancreatic function in alloxan-treated rats,” Archives of Medical Research, vol. 35, no. 2, pp. 114–120, 2004. View at Publisher · View at Google Scholar · View at Scopus
  28. M. Li, J. I. Miyagawa, K. Yamamoto et al., “β cell neogenesis from ducts and phenotypic conversion of residual islet cells in the adult pancreas of glucose intolerant mice induced by selective alloxan perfusion,” Endocrine Journal, vol. 49, no. 5, pp. 561–572, 2002. View at Publisher · View at Google Scholar · View at Scopus
  29. K. Y. Hayashi, H. Tamaki, K. Handa, T. Takahashi, A. Kakita, and S. Yamashina, “Differentiation and proliferation of endocrine cells in the regenerating rat pancreas after 90% pancreatectomy,” Archives of Histology and Cytology, vol. 66, no. 2, pp. 163–174, 2003. View at Publisher · View at Google Scholar · View at Scopus
  30. X. Xu, J. D'Hoker, G. Stangé et al., “Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas,” Cell, vol. 132, no. 2, pp. 197–207, 2008. View at Publisher · View at Google Scholar · View at Scopus
  31. A. Inada, C. Nienaber, H. Katsuta et al., “Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 50, pp. 19915–19919, 2008. View at Publisher · View at Google Scholar · View at Scopus
  32. P. Collombat, X. Xu, P. Ravassard et al., “The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells,” Cell, vol. 138, no. 3, pp. 449–462, 2009. View at Publisher · View at Google Scholar · View at Scopus
  33. J. H. Lee, J. Jo, A. A. Hardikar, V. Periwal, and S. G. Rane, “Cdk4 regulates recruitment of quiescent β-cells and ductal epithelial progenitors to reconstitute β-cell mass,” PLoS ONE, vol. 5, no. 1, Article ID e8653, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. E. Kroon, L. A. Martinson, K. Kadoya et al., “Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo,” Nature Biotechnology, vol. 26, no. 4, pp. 443–452, 2008. View at Publisher · View at Google Scholar · View at Scopus
  35. Q. Zhou, J. Brown, A. Kanarek, J. Rajagopal, and D. A. Melton, “In vivo reprogramming of adult pancreatic exocrine cells to β-cells,” Nature, vol. 455, no. 7213, pp. 627–632, 2008. View at Publisher · View at Google Scholar · View at Scopus
  36. C. H. Chung, E. Hao, R. Piran, E. Keinan, and F. Levine, “Pancreatic β-cell neogenesis by direct conversion from mature α-cells,” Stem Cells, vol. 28, no. 9, pp. 1630–1638, 2010. View at Publisher · View at Google Scholar · View at Scopus
  37. C. H. Chung and F. Levine, “Adult pancreatic alpha-cells: a new source of cells for beta-cell regeneration,” The Review of Diabetic Studies, vol. 7, no. 2, pp. 124–131, 2010. View at Google Scholar · View at Scopus
  38. P. Collombat and A. Mansouri, “Turning on the β-cell identity in the pancreas,” Cell Cycle, vol. 8, no. 21, pp. 3450–3451, 2009. View at Google Scholar · View at Scopus
  39. M. Courtney, A. Pfeifer, K. Al-Hasani et al., “In vivo conversion of adult α-cells into β-like cells: a new research avenue in the context of type 1 diabetes,” Diabetes, Obesity and Metabolism, vol. 13, no. 1, pp. 47–52, 2011. View at Publisher · View at Google Scholar · View at Scopus
  40. P. L. Herrera, “Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages,” Development, vol. 127, no. 11, pp. 2317–2322, 2000. View at Google Scholar · View at Scopus
  41. K. Prasadan, E. Daume, B. Preuett et al., “Glucagon is required for early insulin-positive differentiation in the developing mouse pancreas,” Diabetes, vol. 51, no. 11, pp. 3229–3236, 2002. View at Google Scholar · View at Scopus
  42. P. M. Vuguin, M. H. Kedees, L. Cui et al., “Ablation of the glucagon receptor gene increases fetal lethality and produces alterations in islet development and maturation,” Endocrinology, vol. 147, no. 9, pp. 3995–4006, 2006. View at Publisher · View at Google Scholar · View at Scopus
  43. A. Bhushan, N. Itoh, S. Kato et al., “Fgf10 is essential for maintaining the proliferative capacity of epithelial progenitor cells during early pancreatic organogenesis,” Development, vol. 128, no. 24, pp. 5109–5117, 2001. View at Google Scholar · View at Scopus
  44. U. Ahlgren, S. L. Pfaff, T. M. Jessell, T. Edlund, and H. Edlund, “Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells,” Nature, vol. 385, no. 6613, pp. 257–260, 1997. View at Publisher · View at Google Scholar · View at Scopus
  45. G. Gradwohl, A. Dierich, M. LeMeur, F. Guillemot, and F. Guillemot, “Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 4, pp. 1607–1611, 2000. View at Publisher · View at Google Scholar · View at Scopus
  46. V. M. Schwitzgebel, D. W. Scheel, J. R. Conners et al., “Expression of neurogenin3 reveals an islet cell precursor population in the pancreas,” Development, vol. 127, no. 16, pp. 3533–3542, 2000. View at Google Scholar · View at Scopus
  47. Å. Apelqvist, H. Li, L. Sommer et al., “Notch signalling controls pancreatic cell differentiation,” Nature, vol. 400, no. 6747, pp. 877–881, 1999. View at Publisher · View at Google Scholar · View at Scopus
  48. J. Jensen, E. E. Pedersen, P. Galante et al., “Control of endodermal endocrine development by Hes-1,” Nature Genetics, vol. 24, no. 1, pp. 36–44, 2000. View at Publisher · View at Google Scholar · View at Scopus
  49. J. C. Lee, S. B. Smith, H. Watada et al., “Regulation of the pancreatic pro-endocrine gene neurogenin3,” Diabetes, vol. 50, no. 5, pp. 928–936, 2001. View at Google Scholar · View at Scopus
  50. L. C. Murtaugh, B. Z. Stanger, K. M. Kwan, and D. A. Melton, “Notch signaling controls multiple steps of pancreatic differentiation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 25, pp. 14920–14925, 2003. View at Publisher · View at Google Scholar · View at Scopus
  51. D. Kopinke, M. Brailsford, J. E. Shea, R. Leavitt, C. L. Scaife, and L. C. Murtaugh, “Lineage tracing reveals the dynamic contribution of Hes1+ cells to the developing and adult pancreas,” Development, vol. 138, no. 3, pp. 431–441, 2011. View at Publisher · View at Google Scholar · View at Scopus
  52. H. P. Shih, J. L. Kopp, M. Sandhu, P. A. Seymour, A. Grapin-Botton, and M. Sander, “A Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation,” Development, vol. 139, no. 14, pp. 2488–2499, 2012. View at Publisher · View at Google Scholar
  53. C. Cras-Méneur, L. Li, R. Kopan, and M. A. Permutt, “Presenilins, Notch dose control the fate of pancreatic endocrine progenitors during a narrow developmental window,” Genes and Development, vol. 23, no. 17, pp. 2088–2101, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. E. B. Harmon, Å. A. Apelqvist, N. G. Smart, X. Gu, D. H. Osborne, and S. K. Kim, “GDF11 modulates Ngn3+ islet progenitor cell number and promotes β-cell differentiation in pancreas development,” Development, vol. 131, no. 24, pp. 6163–6174, 2004. View at Publisher · View at Google Scholar · View at Scopus
  55. K. A. Johansson, U. Dursun, N. Jordan et al., “Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types,” Developmental Cell, vol. 12, no. 3, pp. 457–465, 2007. View at Publisher · View at Google Scholar · View at Scopus
  56. J. M. Rukstalis and J. F. Habener, “Neurogenin3: a master regulator of pancreatic islet differentiation and regeneration,” Islets, vol. 1, no. 3, pp. 177–184, 2009. View at Google Scholar · View at Scopus
  57. S. Wang, J. Yan, D. A. Anderson et al., “Neurog3 gene dosage regulates allocation of endocrine and exocrine cell fates in the developing mouse pancreas,” Developmental Biology, vol. 339, no. 1, pp. 26–37, 2010. View at Publisher · View at Google Scholar · View at Scopus
  58. M. Gouzi, Y. H. Kim, K. Katsumoto, K. Johansson, and A. Grapin-Botton, “Neurogenin3 initiates stepwise delamination of differentiating endocrine cells during pancreas development,” Developmental Dynamics, vol. 240, no. 3, pp. 589–604, 2011. View at Publisher · View at Google Scholar · View at Scopus
  59. J. Magenheim, A. M. Klein, R. Ashery-Padan, G. Gu, and Y. Dor, “Ngn3+ endocrine progenitor cells control the fate and morphogenesis of pancreatic ductal epithelium,” Developmental Biology, vol. 359, no. 1, pp. 26–36, 2011. View at Publisher · View at Google Scholar
  60. S. B. Smith, R. Gasa, H. Watada, J. Wang, S. C. Griffen, and M. S. German, “Neurogenin3 and hepatic nuclear factor 1 cooperate in activating pancreatic expression of Pax4,” Journal of Biological Chemistry, vol. 278, no. 40, pp. 38254–38259, 2003. View at Publisher · View at Google Scholar · View at Scopus
  61. S. B. Smith, H. Watada, and M. S. German, “Neurogenin3 activates the islet differentiation program while repressing its own expression,” Molecular Endocrinology, vol. 18, no. 1, pp. 142–149, 2004. View at Publisher · View at Google Scholar · View at Scopus
  62. H. P. Huang, M. Liu, H. M. El-Hodiri, K. Chu, M. Jamrich, and M. J. Tsai, “Regulation of the pancreatic islet-specific gene BETA2 (neuroD) by neurogenin 3,” Molecular and Cellular Biology, vol. 20, no. 9, pp. 3292–3307, 2000. View at Publisher · View at Google Scholar · View at Scopus
  63. G. Mellitzer, S. Bonné, R. F. Luco et al., “IA1 is NGN3-dependent and essential for differentiation of the endocrine pancreas,” EMBO Journal, vol. 25, no. 6, pp. 1344–1352, 2006. View at Publisher · View at Google Scholar · View at Scopus
  64. R. Desgraz and P. L. Herrera, “Pancreatic neurogenin 3-expressing cells are unipotent islet precursors,” Development, vol. 136, no. 21, pp. 3567–3574, 2009. View at Publisher · View at Google Scholar · View at Scopus
  65. P. A. Seymour, K. K. Freude, M. N. Tran et al., “SOX9 is required for maintenance of the pancreatic progenitor cell pool,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 6, pp. 1865–1870, 2007. View at Publisher · View at Google Scholar · View at Scopus
  66. P. A. Seymour, K. K. Freude, C. L. Dubois, H. P. Shih, N. A. Patel, and M. Sander, “A dosage-dependent requirement for Sox9 in pancreatic endocrine cell formation,” Developmental Biology, vol. 323, no. 1, pp. 19–30, 2008. View at Publisher · View at Google Scholar · View at Scopus
  67. N. Sander, L. Sussel, J. Conners et al., “Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of β-cell formation in the pancreas,” Development, vol. 127, no. 24, pp. 5533–5540, 2000. View at Google Scholar · View at Scopus
  68. A. E. Schaffer, K. K. Freude, S. B. Nelson, and M. Sander, “Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors,” Developmental Cell, vol. 18, no. 6, pp. 1022–1029, 2010. View at Google Scholar · View at Scopus
  69. M. A. Maestro, S. F. Boj, R. F. Luco et al., “Hnf6 and Tcf2 (MODY5) are linked in a gene network operating in a precursor cell domain of the embryonic pancreas,” Human Molecular Genetics, vol. 12, no. 24, pp. 3307–3314, 2003. View at Publisher · View at Google Scholar · View at Scopus
  70. M. Maestro, C. Cardalda, S. Boj, R. Luco, J. Servitja, and J. Ferrer, “Distinct roles of HNF1β, HNF1α, and HNF4α in regulating pancreas development, β-cell function and growth,” Endocrine Development, vol. 12, pp. 33–45, 2007. View at Publisher · View at Google Scholar · View at Scopus
  71. M. Solar, C. Cardalda, I. Houbracken et al., “Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth,” Developmental Cell, vol. 17, no. 6, pp. 849–860, 2009. View at Publisher · View at Google Scholar · View at Scopus
  72. J. L. Kopp, C. L. Dubois, E. Hao, F. Thorel, P. L. Herrera, and M. Sander, “Progenitor cell domains in the developing and adult pancreas,” Cell Cycle, vol. 10, no. 12, pp. 1921–1927, 2011. View at Publisher · View at Google Scholar · View at Scopus
  73. S. Wang, J. N. Jensen, P. A. Seymour et al., “Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 24, pp. 9715–9720, 2009. View at Publisher · View at Google Scholar · View at Scopus
  74. F. J. Naya, H. P. Huang, Y. Qiu et al., “Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/NeuroD-deficient mice,” Genes and Development, vol. 11, no. 18, pp. 2323–2334, 1997. View at Google Scholar · View at Scopus
  75. M. S. Gierl, N. Karoulias, H. Wende, M. Strehle, and C. Birchmeier, “The Zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic β cells and intestinal endocrine cells,” Genes and Development, vol. 20, no. 17, pp. 2465–2478, 2006. View at Publisher · View at Google Scholar · View at Scopus
  76. J. Soyer, L. Flasse, W. Raffelsberger et al., “Rfx6 is an Ngn3-dependent winged helix transcription factor required for pancreatic islet cell development,” Development, vol. 137, no. 2, pp. 203–212, 2010. View at Publisher · View at Google Scholar · View at Scopus
  77. S. B. Smith, H. Q. Qu, N. Taleb et al., “Rfx6 directs islet formation and insulin production in mice and humans,” Nature, vol. 463, no. 7282, pp. 775–780, 2010. View at Publisher · View at Google Scholar · View at Scopus
  78. B. Sosa-Pineda, K. Chowdhury, M. Torres, G. Oliver, and P. Gruss, “The Pax4 gene is essential for differentiation of insulin-producing β cells in the mammalian pancreas,” Nature, vol. 386, no. 6623, pp. 399–402, 1997. View at Publisher · View at Google Scholar · View at Scopus
  79. J. Wang, L. Elghazi, S. E. Parker et al., “The concerted activities of Pax4 and Nkx2.2 are essential to initiate pancreatic β-cell differentiation,” Developmental Biology, vol. 266, no. 1, pp. 178–189, 2004. View at Publisher · View at Google Scholar · View at Scopus
  80. A. L. Greenwood, S. Li, K. Jones, and D. A. Melton, “Notch signaling reveals developmental plasticity of Pax4+ pancreatic endocrine progenitors and shunts them to a duct fate,” Mechanisms of Development, vol. 124, no. 2, pp. 97–107, 2007. View at Publisher · View at Google Scholar · View at Scopus
  81. P. Collombat, A. Mansouri, J. Hecksher-Sørensen et al., “Opposing actions of Arx and Pax4 in endocrine pancreas development,” Genes and Development, vol. 17, no. 20, pp. 2591–2603, 2003. View at Publisher · View at Google Scholar · View at Scopus
  82. P. Collombat, J. Hecksher-Sørensen, V. Broccoli et al., “The simultaneous loss of Arx and Pax4 genes promotes a somatostatin-producing cell fate specification at the expense of the α- and β-cell lineages in the mouse endocrine pancreas,” Development, vol. 132, no. 13, pp. 2969–2980, 2005. View at Publisher · View at Google Scholar · View at Scopus
  83. S. Dhawan, S. Georgia, S. I. Tschen, G. Fan, and A. Bhushan, “Pancreatic beta cell identity is maintained by DNA methylation-mediated repression of Arx,” Developmental Cell, vol. 20, no. 4, pp. 419–429, 2011. View at Publisher · View at Google Scholar · View at Scopus
  84. J. Liu, C. S. Hunter, A. Du et al., “Islet-1 regulates Arx transcription during pancreatic islet α-cell development,” Journal of Biological Chemistry, vol. 286, no. 17, pp. 15352–15360, 2011. View at Publisher · View at Google Scholar · View at Scopus
  85. P. Collombat, J. Hecksher-Sørensen, J. Krull et al., “Embryonic endocrine pancreas and mature β cells acquire α and PP cell phenotypes upon Arx misexpression,” Journal of Clinical Investigation, vol. 117, no. 4, pp. 961–970, 2007. View at Publisher · View at Google Scholar · View at Scopus
  86. L. Sussel, J. Kalamaras, D. J. Hartigan-O'Connor et al., “Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic β cells,” Development, vol. 125, no. 12, pp. 2213–2221, 1998. View at Google Scholar · View at Scopus
  87. C. S. Chao, Z. L. Loomis, J. E. Lee, and L. Sussel, “Genetic identification of a novel NeuroD1 function in the early differentiation of islet α, PP and ε cells,” Developmental Biology, vol. 312, no. 2, pp. 523–532, 2007. View at Publisher · View at Google Scholar · View at Scopus
  88. S. Kordowich, P. Collombat, and A. Mansouri, “Arx and Nkx2.2 compound deficiency redirects pancreatic alpha- and beta-cell differentiation to a somatostatin/ghrelin co-expressing cell lineage,” BMC Developmental Biology, vol. 11, article 52, 2011. View at Publisher · View at Google Scholar
  89. T. L. Mastraccia, C. L. Wilcoxb, L. Arnes et al., “Nkx2.2 and Arx genetically interact to regulate pancreatic endocrine cell development and endocrine hormone expression,” Developmental Biology, vol. 359, no. 1, pp. 1–11, 2011. View at Publisher · View at Google Scholar
  90. J. B. Papizan, R. A. Singer, S.-I. Tschen et al., “Nkx2.2 repressor complex regulates islet β-cell specification and prevents β-to-α-cell reprogramming,” Genes and Development, vol. 25, no. 21, pp. 2291–2305, 2011. View at Publisher · View at Google Scholar
  91. Y. Hang and R. Stein, “MafA and MafB activity in pancreatic β cells,” Trends in Endocrinology and Metabolism, vol. 22, no. 9, pp. 364–373, 2011. View at Publisher · View at Google Scholar
  92. I. Artner, Y. Hang, M. Mazur et al., “MafA and MafB regulate genes critical to β-cells in a unique temporal manner,” Diabetes, vol. 59, no. 10, pp. 2530–2539, 2010. View at Publisher · View at Google Scholar · View at Scopus
  93. I. Artner, J. Le Lay, Y. Hang et al., “An activator of the glucagon gene expressed in developing islet α- and β-cells,” Diabetes, vol. 55, no. 2, pp. 297–304, 2006. View at Publisher · View at Google Scholar · View at Scopus
  94. W. Nishimura, T. Kondo, T. Salameh et al., “A switch from MafB to MafA expression accompanies differentiation to pancreatic β-cells,” Developmental Biology, vol. 293, no. 2, pp. 526–539, 2006. View at Publisher · View at Google Scholar · View at Scopus
  95. Y. Abiko, M. Saitoh, M. Nishimura, M. Yamazaki, D. Sawamura, and T. Kaku, “Role of β-defensins in oral epithelial health and disease,” Medical Molecular Morphology, vol. 40, no. 4, pp. 179–184, 2007. View at Publisher · View at Google Scholar · View at Scopus
  96. L. St-Onge, B. Sosa-Pineda, K. Chowdhury, A. Mansouri, and P. Gruss, “Pax6 is required for differentiation of glucagon-producing α-cells in mouse pancreas,” Nature, vol. 387, no. 6631, pp. 406–409, 1997. View at Publisher · View at Google Scholar · View at Scopus
  97. M. Sander, A. Neubüser, J. Kalamaras, H. C. Ee, G. R. Martin, and M. S. German, “Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development,” Genes and Development, vol. 11, no. 13, pp. 1662–1673, 1997. View at Google Scholar · View at Scopus
  98. R. S. Heller, M. Jenny, P. Collombat et al., “Genetic determinants of pancreatic ε-cell development,” Developmental Biology, vol. 286, no. 1, pp. 217–224, 2005. View at Publisher · View at Google Scholar · View at Scopus
  99. R. Ashery-Padan, X. Zhou, T. Marquardt et al., “Conditional inactivation of Pax6 in the pancreas causes early onset of diabetes,” Developmental Biology, vol. 269, no. 2, pp. 479–488, 2004. View at Publisher · View at Google Scholar · View at Scopus
  100. J. C. Schisler, P. T. Fueger, D. A. Babu et al., “Stimulation of human and rat islet β-cell proliferation with retention of function by the homeodomain transcription factor Nkx6.1,” Molecular and Cellular Biology, vol. 28, no. 10, pp. 3465–3476, 2008. View at Publisher · View at Google Scholar · View at Scopus
  101. A. E. Schaffer, A. J. Yang, F. Thorel, P. L. Herrera, and M. Sander, “Transgenic overexpression of the transcription factor Nkx6.1 in β-cells of mice does not increase β-cell proliferation, β-cell mass, or improve glucose clearance,” Molecular Endocrinology, vol. 25, no. 11, pp. 1904–1914, 2011. View at Publisher · View at Google Scholar
  102. T. Brun, I. Franklin, L. St.-Onge L. et al., “The diabetes-linked transcription factor PAX4 promotes β-cell proliferation and survival in rat and human islets,” Journal of Cell Biology, vol. 167, no. 6, pp. 1123–1135, 2004. View at Publisher · View at Google Scholar · View at Scopus
  103. A. Du, C. S. Hunter, J. Murray et al., “Islet-1 is required for the maturation, proliferation, and survival of the endocrine pancreas,” Diabetes, vol. 58, no. 9, pp. 2059–2069, 2009. View at Publisher · View at Google Scholar · View at Scopus
  104. U. Ahlgren, J. Jonsson, L. Jonsson, K. Simu, and H. Edlund, “β-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the β-cell phenotype and maturity onset diabetes,” Genes and Development, vol. 12, no. 12, pp. 1763–1768, 1998. View at Google Scholar · View at Scopus
  105. Y.-P. Yang, F. Thorel, D. F. Boyer, P. L. Herrera, and C. V. E. Wright, “Context-specific αa-to-β-cell reprogramming by forced Pdx1 expression,” Genes and Development, vol. 25, no. 16, pp. 1680–1685, 2011. View at Publisher · View at Google Scholar
  106. S. Bonner-Weir, W. C. Li, L. Ouziel-Yahalom, L. Guo, G. C. Weir, and A. Sharma, “β-cell growth and regeneration: replication is only part of the story,” Diabetes, vol. 59, no. 10, pp. 2340–2348, 2010. View at Publisher · View at Google Scholar · View at Scopus
  107. R. Desgraz, C. Bonal, and P. L. Herrera, “β-Cell regeneration: the pancreatic intrinsic faculty,” Trends in Endocrinology and Metabolism, vol. 22, no. 1, pp. 34–43, 2011. View at Publisher · View at Google Scholar · View at Scopus
  108. B. M. Desai, J. Oliver-Krasinski, D. D. De Leon et al., “Preexisting pancreatic acinar cells contribute to acinar cell, but not islet β cell, regeneration,” Journal of Clinical Investigation, vol. 117, no. 4, pp. 971–977, 2007. View at Publisher · View at Google Scholar · View at Scopus
  109. H. Mashima, H. Ohnishi, K. Wakabayashi et al., “Betacellulin and activin A coordinately convert amylase-secreting pancreatic AR42J cells into insulin-secreting cells,” Journal of Clinical Investigation, vol. 97, no. 7, pp. 1647–1654, 1996. View at Google Scholar · View at Scopus
  110. H. Mashima, H. Shibata, T. Mine, and I. Kojima, “Formation of insulin-producing cells from pancreatic acinar AR42J cells by hepatocyte growth factor,” Endocrinology, vol. 137, no. 9, pp. 3969–3976, 1996. View at Publisher · View at Google Scholar · View at Scopus
  111. M. Rovira, S. G. Scott, A. S. Liss, J. Jensen, S. P. Thayer, and S. D. Leach, “Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 1, pp. 75–80, 2010. View at Publisher · View at Google Scholar · View at Scopus
  112. D. Hesselson, R. M. Anderson, and D. Y. R. Stainier, “Suppression of Ptf1a activity induces acinar-to-endocrine conversion,” Current Biology, vol. 21, no. 8, pp. 712–717, 2011. View at Publisher · View at Google Scholar · View at Scopus
  113. S. Georgia and A. Bhushan, “β cell replication is the primary mechanism for maintaining postnatal β cell mass,” Journal of Clinical Investigation, vol. 114, no. 7, pp. 963–968, 2004. View at Publisher · View at Google Scholar · View at Scopus
  114. D. A. Cano, I. C. Rulifson, P. W. Heiser et al., “Regulated β-cell regeneration in the adult mouse pancreas,” Diabetes, vol. 57, no. 4, pp. 958–966, 2008. View at Publisher · View at Google Scholar · View at Scopus
  115. C. S. Lee, D. D. De León, K. H. Kaestner, and D. A. Stoffers, “Regeneration of pancreatic islets after partial pancreatectomy in mice does not involve the reactivation of neurogenin-3,” Diabetes, vol. 55, no. 2, pp. 269–272, 2006. View at Google Scholar · View at Scopus
  116. M. V. Joglekar, V. S. Parekh, S. Mehta, R. R. Bhonde, and A. A. Hardikar, “MicroRNA profiling of developing and regenerating pancreas reveal post-transcriptional regulation of neurogenin3,” Developmental Biology, vol. 311, no. 2, pp. 603–612, 2007. View at Publisher · View at Google Scholar · View at Scopus
  117. S. Rieck and K. H. Kaestner, “Expansion of β-cell mass in response to pregnancy,” Trends in Endocrinology and Metabolism, vol. 21, no. 3, pp. 151–158, 2010. View at Publisher · View at Google Scholar · View at Scopus
  118. S. K. Karnik, H. Chen, G. W. McLean et al., “Menin controls growth of pancreatic β-cells in pregnant mice and promotes gestational diabetes mellitus,” Science, vol. 318, no. 5851, pp. 806–809, 2007. View at Publisher · View at Google Scholar · View at Scopus
  119. S. Abouna, R. W. Old, S. Pelengaris et al., “Non-β-cell progenitors of β-cells in pregnant mice,” Organogenesis, vol. 6, no. 2, pp. 125–133, 2010. View at Google Scholar · View at Scopus
  120. M. Teta, S. Y. Long, L. M. Wartschow, M. M. Rankin, and J. A. Kushner, “Very slow turnover of β-cells in aged adult mice,” Diabetes, vol. 54, no. 9, pp. 2557–2567, 2005. View at Publisher · View at Google Scholar · View at Scopus
  121. K. Tanigawa, S. Nakamura, M. Kawaguchi, G. Xu, S. Kin, and K. Tamura, “Effect of aging on B-cell function and replication in rat pancreas after 90% pancreatectomy,” Pancreas, vol. 15, no. 1, pp. 53–59, 1997. View at Google Scholar · View at Scopus
  122. S. I. Tschen, S. Dhawan, T. Gurlo, and A. Bhushan, “Age-dependent decline in β-cell proliferation restricts the capacity of β-cell regeneration in mice,” Diabetes, vol. 58, no. 6, pp. 1312–1320, 2009. View at Publisher · View at Google Scholar · View at Scopus
  123. M. M. Rankin and J. A. Kushner, “Adaptive β-cell proliferation is severely restricted with advanced age,” Diabetes, vol. 58, no. 6, pp. 1365–1372, 2009. View at Publisher · View at Google Scholar · View at Scopus
  124. J. A. Kushner, M. A. Ciemerych, E. Sicinska et al., “Cyclins D2 and D1 are essential for postnatal pancreatic β-cell growth,” Molecular and Cellular Biology, vol. 25, no. 9, pp. 3752–3762, 2005. View at Publisher · View at Google Scholar · View at Scopus
  125. I. Cozar-Castellano, N. Fiaschi-Taesch, T. A. Bigatel et al., “Molecular control of cell cycle progression in the pancreatic β-cell,” Endocrine Reviews, vol. 27, no. 4, pp. 356–370, 2006. View at Publisher · View at Google Scholar · View at Scopus
  126. I. Cozar-Castellano, K. K. Takane, R. Bottino, A. N. Balamurugan, and A. F. Stewart, “Induction of beta-cell proliferation and retinoblastoma protein phosphorylation in rat and human islets using adenovirus-mediated transfer of cyclin-dependent kinase-4 and cyclin D1,” Diabetes, vol. 53, no. 1, pp. 149–159, 2004. View at Publisher · View at Google Scholar · View at Scopus
  127. S. Bonner-Weir, L. A. Baxter, G. T. Schuppin, and F. E. Smith, “A second pathway for regeneration of adult exocrine and endocrine pancreas: a possible recapitulation of embryonic development,” Diabetes, vol. 42, no. 12, pp. 1715–1720, 1993. View at Google Scholar · View at Scopus
  128. Y. Dor and D. A. Melton, “Facultative endocrine progenitor cells in the adult pancreas,” Cell, vol. 132, no. 2, pp. 183–184, 2008. View at Publisher · View at Google Scholar · View at Scopus
  129. H. P. Huang, K. Chu, E. Nemoz-Gaillard, D. Elberg, and M. J. Tsai, “Neogenesis of β-cells in adult BETA2/NeuroD-deficient mice,” Molecular Endocrinology, vol. 16, no. 3, pp. 541–551, 2002. View at Publisher · View at Google Scholar · View at Scopus
  130. J. A. Kushner, G. C. Weir, and S. Bonner-Weir, “Ductal origin hypothesis of pancreatic regeneration under attack,” Cell Metabolism, vol. 11, no. 1, pp. 2–3, 2010. View at Publisher · View at Google Scholar · View at Scopus
  131. D. Kopinke and L. C. Murtaugh, “Exocrine-to-endocrine differentiation is detectable only prior to birth in the uninjured mouse pancreas,” BMC Developmental Biology, vol. 10, article 38, 2010. View at Publisher · View at Google Scholar · View at Scopus
  132. J. L. Kopp, C. L. Dubois, A. E. Schaffer et al., “Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas,” Development, vol. 138, no. 4, pp. 653–665, 2011. View at Publisher · View at Google Scholar · View at Scopus
  133. M. Reichert and A. K. Rustgi, “Pancreatic ductal cells in development, regeneration, and neoplasia,” Journal of Clinical Investigation, vol. 121, no. 12, pp. 4572–4578, 2011. View at Publisher · View at Google Scholar
  134. R. W. Gelling, X. Q. Du, D. S. Dichmann et al., “Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 3, pp. 1438–1443, 2003. View at Publisher · View at Google Scholar · View at Scopus
  135. M. Furuta, H. Yano, A. Zhou et al., “Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 13, pp. 6646–6651, 1997. View at Publisher · View at Google Scholar · View at Scopus
  136. Y. Hayashi, M. Yamamoto, H. Mizoguchi et al., “Mice deficient for glucagon gene-derived peptides display normoglycemia and hyperplasia of islet α-cells but not of intestinal L-cells,” Molecular Endocrinology, vol. 23, no. 12, pp. 1990–1999, 2009. View at Publisher · View at Google Scholar · View at Scopus
  137. G. C. Webb, M. S. Akbar, C. Zhao, H. H. Swift, and D. F. Steiner, “Glucagon replacement via micro-osmotic pump corrects hypoglycemia and α-cell hyperplasia in prohormone convertase 2 knockout mice,” Diabetes, vol. 51, no. 2, pp. 398–405, 2002. View at Google Scholar · View at Scopus
  138. M. Vincent, Y. Guz, M. Rozenberg et al., “Abrogation of protein convertase 2 activity results in delayed islet cell differentiation and maturation, increased α-cell proliferation, and islet neogenesis,” Endocrinology, vol. 144, no. 9, pp. 4061–4069, 2003. View at Publisher · View at Google Scholar · View at Scopus
  139. F. Thorel, N. Damond, S. Chera, A. Wiederkehr, C. B. Wollheim, and P. L. Herrera, “Normal glucagon signaling and β-cell function after near-total α-cell ablation in adult mice,” Diabetes, vol. 60, no. 11, pp. 2872–2882, 2011. View at Publisher · View at Google Scholar
  140. J. Lu, P. L. Herrera, C. Carreira et al., “Alpha cell-specific Men1 ablation triggers the transdifferentiation of glucagon-expressing cells and insulinoma development,” Gastroenterology, vol. 138, no. 5, pp. 1954–1965, 2010. View at Publisher · View at Google Scholar · View at Scopus
  141. Z. Liu and J. F. Habener, “Alpha cells beget beta cells,” Cell, vol. 138, no. 3, pp. 424–426, 2009. View at Publisher · View at Google Scholar · View at Scopus
  142. Z. Liu, W. Kim, Z. Chen et al., “Insulin and glucagon regulate pancreatic α-cell proliferation,” PLoS ONE, vol. 6, no. 1, Article ID e16096, 2011. View at Publisher · View at Google Scholar · View at Scopus
  143. W. Gepts and J. De Mey, “Islet cell survival determined by morphology. An immunocytochemical study of the islets of Langerhans in juvenile diabetes mellitus,” Diabetes, vol. 27, no. 1, pp. 251–261, 1978. View at Google Scholar · View at Scopus
  144. Z. Li, F. A. Karlsson, and S. Sandler, “Islet loss and alpha cell expansion in type 1 diabetes induced by multiple low-dose streptozotocin administration in mice,” Journal of Endocrinology, vol. 165, no. 1, pp. 93–99, 2000. View at Google Scholar · View at Scopus
  145. J. F. Habener and V. Stanojevic, “α-cell role in β-cell generation and regeneration,” Islets, vol. 4, no. 3, pp. 188–198, 2012. View at Publisher · View at Google Scholar