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Development, Vol 127, Issue 16 3533-3542, Copyright © 2000 by Company of Biologists

JOURNAL ARTICLES

Expression of neurogenin3 reveals an islet cell precursor population in the pancreas

VM Schwitzgebel, DW Scheel, JR Conners, J Kalamaras, JE Lee, DJ Anderson, L Sussel, JD Johnson and MS German
Hormone Research Institute, Department of Pediatrics, and Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.

Differentiation of early gut endoderm cells into the endocrine cells forming the pancreatic islets of Langerhans depends on a cascade of gene activation events controlled by transcription factors including the basic helix-loop-helix (bHLH) proteins. To delineate this cascade, we began by establishing the position of neurogenin3, a bHLH factor found in the pancreas during fetal development. We detect neurogenin3 immunoreactivity transiently in scattered ductal cells in the fetal mouse pancreas, peaking at embryonic day 15.5. Although not detected in cells expressing islet hormones or the islet transcription factors Isl1, Brn4, Pax6 or PDX1, neurogenin3 is detected along with early islet differentiation factors Nkx6.1 and Nkx2.2, establishing that it is expressed in immature cells in the islet lineage. Analysis of transcription factor-deficient mice demonstrates that neurogenin3 expression is not dependent on neuroD1/BETA2, Mash1, Nkx2.2, Nkx6.1, or Pax6. Furthermore, early expression of neurogenin3 under control of the Pdx1 promoter is alone sufficient to drive early and ectopic differentiation of islet cells, a capability shared by the pancreatic bHLH factor, neuroD1/BETA2, but not by the muscle bHLH factor, MyoD. However, the islet cells produced in these transgenic experiments are overwhelmingly (alpha) cells, suggesting that factors other than the bHLH factors are required to deviate from a default * cell fate. These data support a model in which neurogenin3 acts upstream of other islet differentiation factors, initiating the differentiation of endocrine cells, but switching off prior to final differentiation. The ability to uniquely identify islet cell precursors by neurogenin3 expression allows us to determine the position of other islet transcription factors in the differentiation cascade and to propose a map for the islet cell differentiation pathway.
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J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3475 - 3485.
[Abstract] [Full Text] [PDF]

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J.-W. Kim, V. Seghers, J.-H. Cho, Y. Kang, S. Kim, Y. Ryu, K. Baek, L. Aguilar-Bryan, Y.-D. Lee, J. Bryan, et al.
Transactivation of the Mouse Sulfonylurea Receptor I Gene by BETA2/NeuroD
Mol. Endocrinol., May 1, 2002; 16(5): 1097 - 1107.
[Abstract] [Full Text] [PDF]

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S. K. Chakrabarti, J. C. James, and R. G. Mirmira
Quantitative Assessment of Gene Targeting in Vitro and in Vivo by the Pancreatic Transcription Factor, Pdx1. IMPORTANCE OF CHROMATIN STRUCTURE IN DIRECTING PROMOTER BINDING
J. Biol. Chem., April 5, 2002; 277(15): 13286 - 13293.
[Abstract] [Full Text] [PDF]

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 Nucleic Acids ResHome page
M. B. Breslin, M. Zhu, A. L. Notkins, and M. S. Lan
Neuroendocrine differentiation factor, IA-1, is a transcriptional repressor and contains a specific DNA-binding domain: identification of consensus IA-1 binding sequence
Nucleic Acids Res., February 15, 2002; 30(4): 1038 - 1045.
[Abstract] [Full Text] [PDF]

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 DevelopmentHome page
A. Bhushan, N. Itoh, S. Kato, J. P. Thiery, P. Czernichow, S. Bellusci, and R. Scharfmann
Fgf10 is essential for maintaining the proliferative capacity of epithelial progenitor cells during early pancreatic organogenesis
Development, December 15, 2001; 128(24): 5109 - 5117.
[Abstract] [Full Text] [PDF]

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 JCBHome page
C. L. Pin, J. M. Rukstalis, C. Johnson, and S. F. Konieczny
The bHLH transcription factor Mist1 is required to maintain exocrine pancreas cell organization and acinar cell identity
J. Cell Biol., November 12, 2001; 155(4): 519 - 530.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
A. Abderrahmani, M. Steinmann, V. Plaisance, G. Niederhauser, J.-A. Haefliger, V. Mooser, C. Bonny, P. Nicod, and G. Waeber
The Transcriptional Repressor REST Determines the Cell-Specific Expression of the Human MAPK8IP1 Gene Encoding IB1 (JIP-1)
Mol. Cell. Biol., November 1, 2001; 21(21): 7256 - 7267.
[Abstract] [Full Text] [PDF]

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 DiabetesHome page
S. Assady, G. Maor, M. Amit, J. Itskovitz-Eldor, K. L. Skorecki, and M. Tzukerman
Insulin Production by Human Embryonic Stem Cells
Diabetes, August 1, 2001; 50(8): 1691 - 1697.
[Abstract] [Full Text] [PDF]

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 DiabetesHome page
J. C. Lee, S. B. Smith, H. Watada, J. Lin, D. Scheel, J. Wang, R. G. Mirmira, and M. S. German
Regulation of the Pancreatic Pro-Endocrine Gene Neurogenin3
Diabetes, May 1, 2001; 50(5): 928 - 936.
[Abstract] [Full Text]

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 DiabetesHome page
L. del Bosque-Plata, J. Lin, Y. Horikawa, P. E.H. Schwarz, N. J. Cox, N. Iwasaki, M. Ogata, Y. Iwamoto, M. S. German, and G. I. Bell
Mutations in the Coding Region of the Neurogenin 3 Gene (NEUROG3) Are Not a Common Cause of Maturity-Onset Diabetes of the Young in Japanese Subjects
Diabetes, March 1, 2001; 50(3): 694 - 696.
[Abstract] [Full Text]

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 Genes Dev.Home page
A. Grapin-Botton, A. R. Majithia, and D. A. Melton
Key events of pancreas formation are triggered in gut endoderm by ectopic expression of pancreatic regulatory genes
Genes & Dev., February 15, 2001; 15(4): 444 - 454.
[Abstract] [Full Text]

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 Genes Dev.Home page
S. K. Kim and M. Hebrok
Intercellular signals regulating pancreas development and function
Genes & Dev., January 15, 2001; 15(2): 111 - 127.
[Full Text]

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 DevelopmentHome page
M Sander, L Sussel, J Conners, D Scheel, J Kalamaras, F Dela Cruz, V Schwitzgebel, A Hayes-Jordan, and M German
Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas
Development, January 12, 2000; 127(24): 5533 - 5540.
[Abstract] [PDF]

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 ScienceHome page
N. Lumelsky, O. Blondel, P. Laeng, I. Velasco, R. Ravin, and R. McKay
Differentiation of Embryonic Stem Cells to Insulin-Secreting Structures Similar to Pancreatic Islets
Science, May 18, 2001; 292(5520): 1389 - 1394.
[Abstract] [Full Text]

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H. Watada, R. G. Mirmira, J. Leung, and M. S. German
Transcriptional and Translational Regulation of beta -Cell Differentiation Factor Nkx6.1
J. Biol. Chem., October 27, 2000; 275(44): 34224 - 34230.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
S. B. Smith, H. Watada, D. W. Scheel, C. Mrejen, and M. S. German
Autoregulation and Maturity Onset Diabetes of the Young Transcription Factors Control the Human PAX4 Promoter
J. Biol. Chem., November 17, 2000; 275(47): 36910 - 36919.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
H. Wang, P. Maechler, B. Ritz-Laser, K. A. Hagenfeldt, H. Ishihara, J. Philippe, and C. B. Wollheim
Pdx1 Level Defines Pancreatic Gene Expression Pattern and Cell Lineage Differentiation
J. Biol. Chem., June 29, 2001; 276(27): 25279 - 25286.
[Abstract] [Full Text] [PDF]


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