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Control of endodermal endocrine development by Hes-1

Nature Genetics volume 24, pages 36–44 (2000)Cite this article

Abstract

Development of endocrine cells in the endoderm involves Atonal and Achaete/Scute-related basic helix-loop-helix (bHLH) proteins. These proteins also serve as neuronal determination and differentiation factors, and are antagonized by the Notch pathway partly acting through Hairy and Enhancer-of-split (HES)-type proteins. Here we show that mice deficient in Hes1 (encoding Hes-1) display severe pancreatic hypoplasia caused by depletion of pancreatic epithelial precursors due to accelerated differentiation of post-mitotic endocrine cells expressing glucagon. Moreover, upregulation of several bHLH components is associated with precocious and excessive differentiation of multiple endocrine cell types in the developing stomach and gut, showing that Hes-1 operates as a general negative regulator of endodermal endocrine differentiation.

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Figure 1: Notch signalling components are expressed in the developing endoderm.
Figure 2: RT–PCR analysis of gene expression in embryonic stomach and intestine (E18).
Figure 3: Upregulation of gene expression in the absence of Hes-1.
Figure 4: Hypoplasia of the pancreas of Hes1 mutants as a result of increased endocrine differentiation.
Figure 5: Histological analysis of late pancreatic development.
Figure 6: Accelerated and excessive formation of multiple endocrine cell types in stomach and duodenum.

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References

  1. 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, 257–260 (1997).

    Article  CAS  Google Scholar 

  2. Jonsson, J., Carlsson, L., Edlund, T. & Edlund, H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 371, 606–609 (1994).

    Article  CAS  Google Scholar 

  3. Sander, M. et al. Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development. Genes Dev. 11, 1662–1673 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. St-Onge, L., Sosa-Pineda, B., Chowdhury, K., Mansouri, A. & Gruss, P. Pax6 is required for differentiation of glucagon-producing α-cells in mouse pancreas. Nature 387, 406–409 (1997).

    Article  CAS  Google Scholar 

  6. Sussel, L. et al. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic β cells. Development 125, 2213–2221 (1998).

    CAS  PubMed  Google Scholar 

  7. Naya, F.J. et al. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in β2/Neurod-deficient mice. Genes Dev. 11, 2323–2334 (1997).

    Article  CAS  Google Scholar 

  8. Borges, M. et al. An achaete-scute homologue essential for neuroendocrine differentiation in the lung. Nature 386, 852– 855 (1997).

    Article  CAS  Google Scholar 

  9. Lee, J.E. et al. Conversion of Xenopus ectoderm into neurons by neurod, a basic helix-loop-helix protein. Science 268, 836 –844 (1995).

    Article  CAS  Google Scholar 

  10. Cau, E., Gradwohl, G., Fode, C. & Guillemot, F. Mash1 activates a cascade of bHLH regulators in olfactory neuron progenitors. Development 124, 1611–1621 (1997).

    CAS  PubMed  Google Scholar 

  11. Guillemot, F. et al. Mammalian achaete-scute homolog-1 is required for the early development of olfactory and autonomic neurons. Cell 75, 463–476 (1993).

    Article  CAS  Google Scholar 

  12. Lee, J.E. Basic helix-loop-helix genes in neural development. Curr. Opin. Neurobiol. 7, 13–20 ( 1997).

    Article  Google Scholar 

  13. Ma, Q.F., Kintner, C. & Anderson, D.J. Identification of neurogenin, a vertebrate neuronal determination gene. Cell 87, 43– 52 (1996).

    Article  CAS  Google Scholar 

  14. Artavanis-Tsakonas, S., Rand, M.D. & Lake, R.J. Notch signaling: cell fate control and signal integration in development. Science 284, 770– 776 (1999).

    Article  CAS  Google Scholar 

  15. Chitnis, A., Henrique, D., Lewis, J., Ishhorowicz, D. & Kintner, C. Primary neurogenesis in Xenopus embryos regulated by a homologue of the Drosophila neurogenic gene-δ. Nature 375, 761–766 ( 1995).

    Article  CAS  Google Scholar 

  16. de la Pompa, J. et al. Conservation of the notch signaling pathway in mammalian neurogenesis . Development 124, 1139– 1148 (1997).

    CAS  PubMed  Google Scholar 

  17. Apelqvist, A. et al. Notch signalling controls pancreatic cell differentiation . Nature 400, 877–881 (1999).

    Article  CAS  Google Scholar 

  18. Jarriault, S. et al. Signalling downstream of activated mammalian notch. Nature 377, 355–358 ( 1995).

    Article  CAS  Google Scholar 

  19. Jarriault, S. et al. Delta-1 activation of notch-1 signaling results in HES-1 transactivation . Mol. Cell. Biol. 18, 7423– 7431 (1998).

    Article  CAS  Google Scholar 

  20. Sasai, Y., Kageyama, R., Tagawa, Y., Shigemoto, R. & Nakanishi, S. 2 mammalian helix loop helix factors structurally related to drosophila hairy and enhancer of split. Genes Dev. 6, 2620–2634 (1992).

    Article  CAS  Google Scholar 

  21. Chen, H. et al. Conservation of the Drosophila lateral inhibition pathway in human lung cancer: a hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression. Proc. Natl Acad. Sci. USA 94, 5355–5360 (1997).

    Article  CAS  Google Scholar 

  22. Ohsako, S., Hyer, J., Panganiban, G., Oliver, I. & Caudy, M. Hairy function as a DNA-binding helix-loop-helix repressor of Drosophila sensory organ formation. Genes Dev. 8 , 2743–2755 (1994).

    Article  CAS  Google Scholar 

  23. Oellers, N., Dehio, M. & Knust, E. bHLH proteins encoded by the Enhancer of split complex of Drosophila negatively interfere with transcriptional activation mediated by proneural genes. Mol. Gen. Genet. 244, 465–473 (1994).

    Article  CAS  Google Scholar 

  24. Ishibashi, M. et al. Persistent expression of helix-loop-helix factor HES-1 prevents mammalian neural differentiation in the central-nervous-system. EMBO J. 13, 1799–1805 ( 1994).

    Article  CAS  Google Scholar 

  25. Ishibashi, M. et al. Targeted disruption of mammalian hairy and enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural-tube defects. Genes Dev. 9, 3136–3148 ( 1995).

    Article  CAS  Google Scholar 

  26. Ohtsuka, T. et al. Hes1 and Hes5 as Notch effectors in mammalian neuronal differentiation . EMBO J. 18, 2196–2207 (1999).

    Article  CAS  Google Scholar 

  27. Jensen, J. et al. Independent development of pancreatic a- and b-cells from Neurogenin-3 expressing precursors. Diabetes (in press).

  28. Wessells, N.K. & Cohen, J.H. Early pancreas morphogenesis: morphogenesis, tissue interations, and mass effects. Dev. Biol. 15, 237–270 ( 1967).

    Article  CAS  Google Scholar 

  29. Øster, A. et al. Rat endocrine pancreatic development in relation to two homeobox gene products (Pdx-1 and Nkx6.1). J. Histochem. Cytochem. 46, 707–715 (1998).

    Article  Google Scholar 

  30. Offield, M.F. et al. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122, 983–995 (1996).

    CAS  PubMed  Google Scholar 

  31. Akazawa, C., Ishibashi, M., Shimizu, C., Nakanishi, S. & Kageyama, R. A mammalian helix-loop-helix factor structurally related to the product of Drosophila proneural gene atonal is a positive transcriptional regulator expressed in the developing nervous system . J. Biol. Chem. 270, 8730– 8738 (1995).

    Article  CAS  Google Scholar 

  32. 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, 1009–1019 ( 1995).

    Article  CAS  Google Scholar 

  33. Sommer, L., Ma, Q.F. & Anderson, D.J. Neurogenins, a novel family of atonal-related bHLH transcription factors, are putative mammalian neuronal determination genes that reveal progenitor-cell heterogeneity in the developing CNS and PNS. Mol. Cell. Neurosci. 8, 221–241 (1996).

    Article  CAS  Google Scholar 

  34. Larsson, L.I., St-Onge, L., Hougaard, D.M., Sosa-Pineda, B. & Gruss, P. Pax4 and 6 regulate gastrointestinal endocrine cell development. Mech. Dev. 79, 153–159 (1998).

    Article  CAS  Google Scholar 

  35. Kaestner, K.H., Silberg, D.G., Traber, P.G. & Schutz, G. The mesenchymal winged helix transcription factor fkh6 is required for the control of gastrointestinal proliferation and differentiation. Genes Dev. 11, 1583–1595 (1997).

    Article  CAS  Google Scholar 

  36. Pabst, O., Schneider, A., Brand, T. & Arnold, H.H. The mouse Nkx2-3 homeodomain gene is expressed in gut mesenchyme during prenatal and postnatal mouse development. Dev. Dyn. 209, 29– 35 (1997).

    Article  CAS  Google Scholar 

  37. Robb, L. et al. Epicardin—a novel basic helix-loop-helix transcription factor gene expressed in epicardium, branchial arch myoblasts, and mesenchyme of developing lung, gut, kidney, and gonads. Dev. Dyn. 213, 105–113 (1998).

    Article  CAS  Google Scholar 

  38. Edlund, H. Transcribing pancreas. Diabetes 47, 1817 –1823 (1998).

    Article  CAS  Google Scholar 

  39. Fisher, A. & Caudy, M. The function of hairy-related bHLH repressor proteins in cell fate decisions. Bioessays 20, 298–306 (1998).

    Article  CAS  Google Scholar 

  40. Valsecchi, V., Ghezzi, C., Ballabio, A. & Rugarli, E.I. Jagged2—a putative notch ligand expressed in the apical ectodermal ridge and in sites of epithelial-mesenchymal interactions. Mech. Dev. 69, 203–207 (1997).

    Article  CAS  Google Scholar 

  41. Beckers, J., Clark, A., Wunsch, K., De-Angelis, M.H. & Gossler, A. Expression of the mouse Delta1 gene during organogenesis and fetal development. Mech. Dev. 84, 165 –168 (1999).

    Article  CAS  Google Scholar 

  42. Mitsiadis, T.A., Henrique, D., Thesleff, I. & Lendahl, U. Mouse serrate-1 (jagged-1)—expression in the developing tooth is regulated by epithelial-mesenchymal interactions and fibroblast growth factor-iv. Development 124, 1473–1483 (1997).

    CAS  PubMed  Google Scholar 

  43. Barbash, D.A. & Cline, T.W. Genetic and molecular analysis of the autosomal component of the primary sex determination signal of Drosophila melanogaster. Genetics 141, 1451– 1471 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Deshpande, G., Stukey, J. & Schedl, P. Scute (sis-b) function in Drosophila sex determination . Mol. Cell. Biol. 15, 4430– 4440 (1995).

    Article  CAS  Google Scholar 

  45. Parkhurst, S.M., Bopp, D. & Ish-Horowicz, D. X:A ratio, the primary sex-determining signal in Drosophila, is transduced by helix-loop-helix proteins. Cell 63 , 1179–1191 (1990).

    Article  CAS  Google Scholar 

  46. Pictet, R. & Rutter, W.J. in Handbook of Physiology, Section 7: Endocrinology, Volume 1 (eds Steiner, D.F. & Freinkel, N.) 25–66 (American Physiological Society, Washington DC, 1972).

    Google Scholar 

  47. Hogan, B., Beddington, R., Costantini, F. & Lacy, E. in Manipulating the Mouse Embryo 303–304 (Cold Spring Harbor Laboratory Press, New York, 1994).

    Google Scholar 

  48. Jensen, J., Serup, P., Karlsen, C., Nielsen, T.F. & Madsen, O.D. mRNA profiling of rat islet tumors reveals Nkx6.1 as a β-cell-specific homeodomain transcription factor. J. Biol. Chem. 271, 18749–18758 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Saule, H. Edlund, J. Rehfeld, A. Buchanan, J. Habener and T. Sudo for antisera, and L. Flores, H.I. Jensen, R. Jørgensen, T. Funder-Nielsen and L. Heller for technical assistance. This work was supported by NIH grant DK-55284 and the Danish National Research Foundation. J.J. is a recipient of a fellowship from the Juvenile Diabetes Foundation International.

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Authors and Affiliations

  1. Department of Developmental Biology, Hagedorn Research Institute, Denmark

    Jan Jensen, Erna Engholm Pedersen, Philip Galante, Jacob Hald, R. Scott Heller & Palle Serup

  2. Institute for Virus Research, Kyoto University, Japan

    Makoto Ishibashi & Ryoichiro Kageyama

  3. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, CU de Strasbourg, France

    Francois Guillemot

  4. Ole D. Madsen

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Correspondence to Ole D. Madsen.

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Jensen, J., Pedersen, E., Galante, P. et al. Control of endodermal endocrine development by Hes-1. Nat Genet 24, 36–44 (2000). https://doi.org/10.1038/71657

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