Seung K. Kim Laboratory








Following are an expanded version of Table 1 and Figure 3 from a review by Kim and Hebrok in Genes & Development:

  • Kim and Hebrok. 2000. Intercellular signals regulating pancreas development and function. Genes Dev 15: 111-127.
The review is available online at http://www.genesdev.org/cgi/content/full/15/2/111.
Please also see Matthias Hebrok's web site.

Note added after publication: Entries for "Pancreatic hypoplasia" in the published article were inadvertantly changed in production and have been amended. We thank Dr. Palle Serup for alerting us to this.

Table 1

Human diseases and candidate disease genes identified by embryologic studies
Disease Genes Intracellular signalling
pathway implicated		 References
1. Annular pancreas Sonic hedgehog,
Indian hedgehog		 Hedgehog Ramalho-Santos et al, 2000;
Hebrok et al, 2000
ActRIIA, ActRIIB, Gdf-1 TGF-ß Kim et al, 2000;
Rankin et al, 2000
 
2. Ectopic pancreas Sonic hedgehog,
Patched		 Hedgehog Kim and Melton, 1998
 
3. Pancreatic hypoplasia
(congenital short pancreas)		 Hes-1, Dll-1 Notch Jensen, et al, 2000b;
Apelqvist et al, 1999
ActRIIA, ActRIIB TGF-ß Kim et al, 2000
 
4. Congenital absence of islets of Langerhans ngn3 Notch Gradwohl at al, 2000;
Wong, et al, 1988;
Dodge, et al, 1977
 
5. Pancreas divisum Sonic hedgehog,
Indian hedgehog		 Hedgehog Hebrok et al, 2000
Smad2 TGF-ß Osborne et al, 2000
 
6. Hyposplenism ActRIIB TGF-ß Oh and Li, 1998
Sonic hedgehog Hedgehog Apelqvist et al, 1997
 
7. Type 2 diabetes mellitus susceptibility,
impaired glucose tolerance		 Patched Hedgehog Hebrok et al, 2000
ActRIIA, ActRIIB TGF-ß Kim et al, 2000;
Osborne et al, 2000
FGFR1c FGF Hart et al, 2000

References Cited in Table

  • Apelqvist, A., U. Ahlgren, and H. Edlund. 1997. Sonic Hedgehog directs specialized mesoderm differentiation in the intestine and pancreas. Current Biology 7: 801-804.
  • Apelqvist, A., H. Li, L. Sommer, P. Beatus, D.J. Anderson, T. Honjo, M. Hrabe de Angelis, U. Lendahl, and H. Edlund. 1999. Notch signalling controls pancreatic cell differentiation. Nature 400: 877-81.
  • Dodge, J. A., and Laurence, K. M. 1977. Congenital absence of islets of Langerhans. Arch Dis Child 52: 411-3.
  • Gradwohl, G., A. Dierich, M. LeMeur, and F. Guillemot. 2000. neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci USA 97: 1607-11.
  • Hart, A. W., N. Baeza, A. Apelqvist, and H. Edlund. 2000. Attenuation of FGF signalling in mouse ß-cells leads to diabetes. Nature 408: 864-868.
  • Hebrok, M., S. K. Kim, B. St.Jacques, A.P. McMahon, and D.A. Melton. 2000. Regulation of pancreas development by Hedgehog signaling. Development 127: 4905-4913.
  • Jensen, J., E. E. Pedersen, P. Galante, J. Hald, R.S. Heller, M. Ishibashi, R. Kageyama, F. Guillemot, P. Serup, and O.D. Madsen. 2000b. Control of endodermal endocrine development by Hes-1. Nat Genet 24: 36-44.
  • Kim, S.K., and D.A. Melton. 1998. Pancreas development is promoted by cyclopamine, a hedgehog signaling inhibitor. Proc Natl Acad Sci USA 95: 13036-13041.
  • Kim, S.K., M. Hebrok, E. Li, S. P. Oh, H. Schrewe, E.B. Harmon, J.S. Lee, and D.A. Melton. 2000. Activin receptor patterning of foregut organogenesis. Genes & Dev. 14: 1866-1871.
  • Oh, S.P., and E. Li. 1997. The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev 11: 1812-1826.
  • Osborne, D., J.S. Lee, E.B. Harmon, A. Ko, A.Y. Zhang, and S.K. Kim. 2000. Smad2 disruption impairs pancreatic ß-cell function and insulin action in mice. Submitted.
  • Ramalho-Santos, M., D.A. Melton, and A.P. McMahon. 2000. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development 127: 2763-2772.
  • Rankin, C.T., T. Bunton, A.M. Lawler, and S.J. Lee. Regulation of left-right patterning in mice by growth/differentiation factor-1. 2000. Nat Genet. 24: 262-5.
  • Schwitzgebel, V.M., D.W. Scheel, J.R. Conners, J. Kalamaras, J.E. Lee, D.J. Anderson, L. Sussel, J.D. Johnson, and M.S. German. 2000. Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development 127: 3533-3542.
  • Wong, K. C., Tse, K., and Chan, J. K. 1988. Congenital absence of insulin-secreting cells. Histopathology 12: 541-5.

Notes

Disruption of type II activin receptor function in mice leads to laterality defects, cardiac defects, hyposplenism, and impaired glucose tolerance (Oh and Li, 1998; Kim et al, 2000). Slavotinek et al (1996) reported an association between diabetes mellitus and laterality defects in humans. Yorifuji et al (1994) reported an association of hereditary cardiac disease, pancreatic hypoplasia and diabetes.

  • Slavotinek, A., E. Hellen, S. Gould, S.B. Coghill, S.M. Huson, and J.A. Hurst. 1996. Three infants of diabetic mothers with malformations of left-right asymmetry - further evidence for the aetiological role of diabetes in this malformation spectrum. Clin Dysmorphol 5: 241-247.
  • Yorifuji T, Matsumura M, Okuno T, Shimizu K, Sonomura T, Muroi J, Kuno C, Takahashi Y, Okuno T. 1994. Hereditary pancreatic hypoplasia, diabetes mellitus, and congenital heart disease: a new syndrome? J Med Genet. 31: 331-333.

Figure 3

Diagram showing regulatory relationships between endocrine-promoting and endocrine-inhibiting factors, with numbers indicating the references to the right.
larger version 		Citations providing evidence for the indicated signaling interaction:
  1. Miralles et al, 1998b.
  2. Sanvito et al, 1994; Hebrok et al, 1998
  3. Kim et al, 2000; Osborne et al, 2001 submitted
  4. Kim et al, 2000; Osborne et al, 2001 submitted; Kim et al, 1997a
  5. Hebrok et al, 1998; Kim and Melton, 1998
  6. Hebrok et al, 2000, but see also article by Thomas et al, 2000
  7. Apelqvist et al, 1999
  8. Jaquemin et al, 2000
  9. Apelqvist et al, 1999; see also Lammert et al, 2000
  10. Jensen et al, 2000b; see also Jensen et al, 2000a

References cited in Figure 3 (also listed in the review article)

  • Hebrok, M., S. K. Kim, and D.A. Melton. 1998. Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev 12: 1705-1713.
  • Hebrok, M., S. K. Kim, B. St.Jacques, A.P. McMahon, and D.A. Melton. 2000. Regulation of pancreas development by Hedgehog signaling. Development 127: 4905-4913.
  • Jacquemin, P., S. M. Durviaux, J. Jensen, C. Godfraind, G. Gradwohl, F. Guillemot, O.D. Madsen, P. Carmeliet, M. Dewerchin, D. Collen, G.G. Rousseau, and F.P. Lemaigre. 2000. 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.
  • Jensen, J., R. S. Heller, T. Funder-Nielsen, E.E. Pedersen, C. Lindsell, G. Weinmaster, O.D. Madsen, and P. Serup. 2000a. Independent development of pancreatic alpha- and beta-cells from neurogenin3-expressing precursors: a role for the notch pathway in repression of premature differentiation. Diabetes 49: 163-76.
  • Jensen, J., E. E. Pedersen, P. Galante, J. Hald, R.S. Heller, M. Ishibashi, R. Kageyama, F. Guillemot, P. Serup, and O.D. Madsen. 2000b. Control of endodermal endocrine development by Hes-1. Nat Genet 24: 36-44.
  • Kim, S.K., M. Hebrok, and D.A. Melton. 1997a. Notochord to endoderm signaling is required for pancreas development. Development 124: 4243-4253.
  • Kim, S.K., and D.A. Melton. 1998. Pancreas development is promoted by cyclopamine, a hedgehog signaling inhibitor. Proc Natl Acad Sci USA 95: 13036-13041.
  • Kim, S.K., M. Hebrok, E. Li, S. P. Oh, H. Schrewe, E.B. Harmon, J.S. Lee, and D.A. Melton. 2000. Activin receptor patterning of foregut organogenesis. Genes & Dev 14: 1866-1871.
  • Lammert, E., J. Brown, and D.A. Melton. 2000. Notch gene expression during pancreatic organogenesis. Mech Dev 94: 199-203.
  • Miralles, F., P. Czernichow, and R. Scharfmann. 1998b. Follistatin regulates the relative proportions of endocrine versus exocrine tissue during pancreatic development. Development 125: 1017-1024.
  • Osborne, D., J.S. Lee, E.B. Harmon, A. Ko, A.Y. Zhang, and S.K. Kim. 2000. Smad2 disruption impairs pancreatic ß-cell function and insulin action in mice. Submitted.
  • Sanvito, F., P. L. Herrera, J. Huarte, A. Nichols, R. Montesano, L. Orci, and J. D. Vassalli. 1994. TGF-ß11 influences the relative development of the exocrine and endocrine pancreas in vitro. Development 120: 3451-3462.
  • Thomas M. K., Rastalsky N., Lee J. H., and Habener J. F. 2000. Hedgehog signaling regulation of insulin production by pancreatic beta-cells. Diabetes 49:2039-47.