The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas
10.1101/gad.12.23.3752
Crossref journal-article
Cold Spring Harbor Laboratory
Genes & Development (246)
Abstract

We have generated a mouse bearing a null allele of the gene encoding basic helix–loop–helix (bHLH) protein p48, the cell-specific DNA-binding subunit of hetero-oligomeric transcription factor PTF1 that directs the expression of genes in the exocrine pancreas. The null mutation, which establishes a lethal condition shortly after birth, leads to a complete absence of exocrine pancreatic tissue and its specific products, indicating that p48 is required for differentiation and/or proliferation of the exocrine cell lineage. p48 is so far the only developmental regulator known to be required exclusively for committing cells to an exocrine fate. The hormone secreting cells of all four endocrine lineages are present in the mesentery that normally harbors the pancreatic organ until day 16 of gestation. Toward the end of embryonic life, cells expressing endocrine functions are no longer detected at their original location but are now found to colonize the spleen, where they persist in a functional state until postnatal death of the organism occurs. These findings suggest that the presence of the exocrine pancreas is required for the correct spatial assembly of the endocrine pancreas and that, in its absence, endocrine cells are directed by default to the spleen, a site that, in some reptiles, harbors part of this particular cellular compartment.

Bibliography

Krapp, A., Knöfler, M., Ledermann, B., Bürki, K., Berney, C., Zoerkler, N., Hagenbüchle, O., & Wellauer, P. K. (1998). The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas. Genes & Development, 12(23), 3752–3763.

Authors 8
  1. Andrea Krapp (first)
  2. Martin Knöfler (additional)
  3. Birgit Ledermann (additional)
  4. Kurt Bürki (additional)
  5. Catherine Berney (additional)
  6. Nicole Zoerkler (additional)
  7. Otto Hagenbüchle (additional)
  8. Peter K. Wellauer (additional)
References 49 Referenced 424
  1. 10.1242/dev.122.5.1409 / Development / The morphogenesis of the pancreatic mesenchyme is uncoupled from that of the pancreatic epithelium in IPF1/PDX1-deficient mice. by Ahlgren (1996)
  2. 10.1038/385257a0 / Nature / Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells. by Ahlgren (1997)
  3. 10.1016/S0960-9822(06)00340-X / Curr. Biol. / Sonic hedgehog directs specialised mesoderm differentiation in the intestine and pancreas. by Apelqvist (1997)
  4. 10.1016/0955-0674(95)80116-2 / Curr. Opin. Cell Biol. / Proteolytic remodeling of extracellular matrix. by Birkedahl-Hansen (1995)
  5. Bradley A. (1987) Production and analysis of chimaeric mice. in Teratocarcinomas and embryonic stem cells: A practical approach, ed Robertson E.J. (IRL Press, Oxford, UK), pp 113–151.
  6. 10.1242/jcs.107.6.1429 / J. Cell Sci. / Expression of neural cell adhesion molecule (N-CAM) in rat islets and its role in islet cell type segregation. by Cirulli (1994)
  7. {'key': '2021111418584029000_12.23.3752.7', 'first-page': '2464', 'article-title': 'Identification of a cell-specific DNA-binding activity that interacts with a transcriptional activator of genes expressed in the acinar pancreas.', 'volume': '9', 'author': 'Cockell', 'year': '1989', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / Identification of a cell-specific DNA-binding activity that interacts with a transcriptional activator of genes expressed in the acinar pancreas. by Cockell (1989)
  8. 10.1128/MCB.15.4.1933 / Mol. Cell. Biol. / Binding sites for hepatocyte nuclear factor 3β or 3α and pancreas transcription factor 1 are required for efficient transcription of the gene encoding pancreatic α-amylase. by Cockell (1995)
  9. 10.1242/dev.122.9.2895 / Development / Cadherins regulate aggregation of pancreatic β cells in vivo. by Dahl (1996)
  10. Falkmer S. (1985) Comparative morphology of pancreatic islets in animals. in The diabetic pancreas, eds Volk B.W. Wellmann K.F. (Plenum Press, New York, NY), pp 17–52. (10.1007/978-1-4757-0348-1_2)
  11. 10.1083/jcb.119.3.493 / J. Cell Biol. / Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. by Gavrieli (1992)
  12. 10.1073/pnas.89.3.1128 / Proc. Natl. Acad. Sci. / Onset of cell-specific gene expression in the developing mouse pancreas. by Gittes (1992)
  13. 10.1242/dev.122.2.439 / Development / Lineage-specific morphogenesis in the developing pancreas: Role of mesenchymal factors. by Gittes (1996)
  14. 10.1055/s-2008-1040401 / Sem. Liver disease / Hepatocyte transplantation: development of new systems for liver repopulation and gene therapy. by Gupta (1992)
  15. 10.1242/dev.121.1.11 / Development / Expression of murine STF-1, a putative insulin gene transcription factor, in β cells of pancreas, duodenal epithelium and pancreatic exocrine and endocrine progenitors during ontogeny. by Guz (1995)
  16. 10.1101/gad.12.11.1705 / Genes & Dev. / Notochord repression of endodermal Sonic hedgehog permits pancreas development. by Hebrok (1997)
  17. {'key': '2021111418584029000_12.23.3752.17', 'first-page': '1151', 'article-title': 'Molecular cloning of mouse pancreatic islet R-cadherin: Differential expression in endocrineand exocrine tissue.', 'volume': '7', 'author': 'Hutton', 'year': '1993', 'journal-title': 'Mol. Endocrinol.'} / Mol. Endocrinol. / Molecular cloning of mouse pancreatic islet R-cadherin: Differential expression in endocrineand exocrine tissue. by Hutton (1993)
  18. 10.1074/jbc.271.31.18749 / J. Biol. Chem. / mRNA profiling of rat islet tumors reveals Nkx 6.1 as a β-cell-specific homeodomain transcription factor. by Jensen (1996)
  19. 10.1038/371606a0 / Nature / Insulin-promoter-factor 1 is required for pancreas development in mice. by Jonsson (1994)
  20. 10.1038/344879a0 / Nature / Insulin gene enhancer protein Isl-1 is a member of a novel class of proteins containing both a homeo- and a Cys-His domain. by Karlsson (1990)
  21. 10.1242/dev.124.21.4243 / Development / Notochord to endoderm signaling is required for pancreas development. by Kim (1997)
  22. 10.1074/jbc.271.36.21993 / J. Biol. Chem. / Constitutive expression of the gene for the cell-specific p48 DNA-binding subunit of pancreas transcription factor 1 in cultured cells is under control of binding sites for transcription factors Sp1 and αCBF. by Knöfler (1996)
  23. 10.1002/j.1460-2075.1996.tb00806.x / EMBO J. / The p48 DNA-binding subunit of transcription factor PTF1 is a new exocrine pancreas-specific basic helix-loop-helix protein. by Krapp (1996)
  24. 10.1093/nar/19.15.4293 / Nucleic Acids. Res. / Simplified mammalian DNA isolation procedure. by Laird (1991)
  25. 10.1016/S0925-4773(96)00609-0 / Mech. Dev. / Pancreatic-duodenal homeobox 1-role in gastric endocrine patterning. by Larsson (1996)
  26. 10.1016/0092-8674(88)90375-3 / Cell / On the origin of pancreatic endocrine cells. by Le Douarin (1988)
  27. {'key': '2021111418584029000_12.23.3752.27', 'first-page': '1275', 'article-title': 'Characterization of somatostatin transactivating factor-1, a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells.', 'volume': '7', 'author': 'Leonard', 'year': '1993', 'journal-title': 'Mol. Endocrinol.'} / Mol. Endocrinol. / Characterization of somatostatin transactivating factor-1, a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells. by Leonard (1993)
  28. 10.1093/nar/20.14.3795 / Nucleic Acids. Res. / A new mouse embryonic stem cell line with good germ line contribution and gene targeting frequency. by Magin (1992)
  29. 10.1002/j.1460-2075.1994.tb06363.x / EMBO J. / IDX-1: A new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene. by Miller (1994)
  30. {'key': '2021111418584029000_12.23.3752.30', 'first-page': '1332', 'article-title': 'Differential expression of neural cell adhesion molecule and cadherins in pancreatic islets, glucagonomas, and insulinomas.', 'volume': '8', 'author': 'Moller', 'year': '1992', 'journal-title': 'Mol. Endocrinol.'} / Mol. Endocrinol. / Differential expression of neural cell adhesion molecule and cadherins in pancreatic islets, glucagonomas, and insulinomas. by Moller (1992)
  31. 10.1101/gad.9.8.1009 / Genes & Dev. / Tissue specific regulation of the insulin gene by a novel basic helix loop helix transcription factor. by Naya (1995)
  32. 10.1101/gad.11.18.2323 / Genes & Dev. / Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/NeuroD-deficient mice. by Naya (1997)
  33. 10.1016/0092-8674(88)90114-6 / Cell / Expressed recombinant cadherins mediate cell sorting in model systems. by Nose (1988)
  34. 10.1016/0092-8674(90)90222-Z / Cell / Localization of specificity determining sites in cadherin cell adhesion molecules. by Nose (1990)
  35. 10.1242/dev.122.3.983 / Development / PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. by Offield (1996)
  36. 10.1002/j.1460-2075.1993.tb06109.x / EMBO J. / IPF1, a homeo-domain containing transactivator of the insulin gene. by Ohlsson (1993)
  37. {'key': '2021111418584029000_12.23.3752.37', 'first-page': '254', 'article-title': 'The DNA-binding activity of transcription factor PTF1 parallels the synthesis of pancreas-specific mRNAs during mouse development.', 'volume': '10', 'author': 'Petrucco', 'year': '1990', 'journal-title': 'Mol. Cell. Biol.'} / Mol. Cell. Biol. / The DNA-binding activity of transcription factor PTF1 parallels the synthesis of pancreas-specific mRNAs during mouse development. by Petrucco (1990)
  38. {'key': '2021111418584029000_12.23.3752.38', 'first-page': '25', 'article-title': 'Development of the embryonic endocrine pancreas.', 'volume': '1', 'author': 'Pictet', 'year': '1972', 'journal-title': 'Handbook of physiology'} / Handbook of physiology / Development of the embryonic endocrine pancreas. by Pictet (1972)
  39. 10.1101/gad.3.10.1613 / Genes & Dev. / The cell-specific transcription factor PTF1 contains two different subunits that interact with the DNA. by Roux (1989)
  40. 10.1016/0022-2836(80)90208-9 / J. Mol. Biol. / Tissue-specific expression of mouse alpha-amylase genes. by Schibler (1980)
  41. 10.1006/excr.1995.1392 / Exp. Cell Res. / Mouse R-cadherin: Expression during the organogenesis of pancreas and gastrointestinal tract. by Sjödin (1995)
  42. 10.1016/0092-8674(91)90371-5 / Cell / Nuclear targeting of the transcription factor PTF1 is mediated by a protein subunit that does not bind to the PTF1 cognate sequence. by Sommer (1991)
  43. 10.1083/jcb.47.1.235 / J. Cell Biol. / The development of the dorsal and ventral pancreas in vivo and in vitro. by Spooner (1970)
  44. 10.1038/386399a0 / Nature / The Pax4 gene is essential for differentiation of insulin-producing β cells in the mammalian pancreas. by Sosa-Pineda (1997)
  45. 10.1038/387406a0 / Nature / Pax6 is required for differentiation of glucagon-producing α-cells in mouse pancreas. by St-Onge (1997)
  46. 10.1016/0092-8674(87)90525-3 / Cell / Formation of heterogenic adherens type junctions between L-CAM containing liver cells and A-CAM containing lens cells. by Volk (1987)
  47. 10.1074/jbc.270.21.12646 / J. Biol. Chem. / The LIM domain homeobox gene isl-1 is a positive regulator of islet cell-specific proglucagon gene transcription. by Wang (1995)
  48. 10.1016/0012-1606(67)90042-5 / Dev. Biol. / Early pancreas organogenesis: Morphogenesis, tissue interactions and mass effects. by Wessells (1967)
  49. {'key': '2021111418584029000_12.23.3752.49', 'first-page': '787', 'article-title': 'XlHbox8: A novel Xenopus homeo protein restricted to a narrow band of endoderm.', 'volume': '104', 'author': 'Wright', 'year': '1988', 'journal-title': 'Development'} / Development / XlHbox8: A novel Xenopus homeo protein restricted to a narrow band of endoderm. by Wright (1988)
Dates
Type When
Created 17 years, 6 months ago (Feb. 20, 2008, 5:15 p.m.)
Deposited 3 years, 9 months ago (Nov. 14, 2021, 10:26 p.m.)
Indexed 1 month ago (Aug. 5, 2025, 9:01 a.m.)
Issued 26 years, 9 months ago (Dec. 1, 1998)
Published 26 years, 9 months ago (Dec. 1, 1998)
Published Online 26 years, 9 months ago (Dec. 1, 1998)
Published Print 26 years, 9 months ago (Dec. 1, 1998)
Funders 0

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@article{Krapp_1998, title={The bHLH protein PTF1-p48 is essential for the formation of the exocrine and the correct spatial organization of the endocrine pancreas}, volume={12}, ISSN={1549-5477}, url={http://dx.doi.org/10.1101/gad.12.23.3752}, DOI={10.1101/gad.12.23.3752}, number={23}, journal={Genes & Development}, publisher={Cold Spring Harbor Laboratory}, author={Krapp, Andrea and Knöfler, Martin and Ledermann, Birgit and Bürki, Kurt and Berney, Catherine and Zoerkler, Nicole and Hagenbüchle, Otto and Wellauer, Peter K.}, year={1998}, month=dec, pages={3752–3763} }