|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
Development, Vol 127, Issue 12 2617-2627, Copyright © 2000 by Company of Biologists
JOURNAL ARTICLES |
PJ Miettinen, M Huotari, T Koivisto, J Ustinov, J Palgi, S Rasilainen, E Lehtonen, J Keski-Oja and T Otonkoski
Department of Pathology and Transplantation Laboratory, The Haartman Institute, and Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland. paivi.miettinen@helsinki.fi
Pancreatic acini and islets are believed to differentiate from common ductal precursors through a process requiring various growth factors. Epidermal growth factor receptor (EGF-R) is expressed throughout the developing pancreas. We have analyzed here the pancreatic phenotype of EGF-R deficient (-/-) mice, which generally die from epithelial immaturity within the first postnatal week. The pancreata appeared macroscopically normal. The most striking feature of the EGF-R (-/-) islets was that instead of forming circular clusters, the islet cells were mainly located in streak-like structures directly associated with pancreatic ducts. Based on BrdU-labelling, proliferation of the neonatal EGF-R (-/-) beta-cells was significantly reduced (2.6+/-0.4 versus 5.8+/-0.9%, P<0.01) and the difference persisted even at 7-11 days of age. Analysis of embryonic pancreata revealed impaired branching morphogenesis and delayed islet cell differentiation in the EGF-R (-/-) mice. Islet development was analyzed further in organ cultures of E12.5 pancreata. The proportion of insulin-positive cells was significantly lower in the EGF-R (-/-) explants (27+/-6 versus 48+/-8%, P<0.01), indicating delayed differentiation of the beta cells. Branching of the epithelium into ducts was also impaired. Matrix metalloproteinase (MMP-2 and MMP-9) activity was reduced 20% in EGF-R (-/-) late-gestation pancreata, as measured by gelatinase assays. Furthermore, the levels of secreted plasminogen activator inhibitor-1 (PAI-1) were markedly higher, while no apparent differences were seen in the levels of active uPA and tPa between EGF-R (-/-) and wild-type pancreata. Our findings suggest that the perturbation of EGF-R-mediated signalling can lead to a generalized proliferation defect of the pancreatic epithelia associated with a delay in beta cell development and disturbed migration of the developing islet cells as they differentiate from their precursors. Upregulated PAI-1 production and decreased gelatinolytic activity correlated to this migration defect. An intact EGF-R pathway appears to be a prerequisite for normal pancreatic development.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  T. Yoshida, N. Shiraki, H. Baba, M. Goto, S. Fujiwara, K. Kume, and S. Kume Expression patterns of epiplakin1 in pancreas, pancreatic cancer and regenerating pancreas. Genes Cells, July 1, 2008; 13(7): 667 - 678. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ivkovic, P. Canoll, and J. E. Goldman Constitutive EGFR Signaling in Oligodendrocyte Progenitors Leads to Diffuse Hyperplasia in Postnatal White Matter J. Neurosci., January 23, 2008; 28(4): 914 - 922. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M C Pustovrh, A Jawerbaum, V White, E Capobianco, R Higa, N Martinez, J J Lopez-Costa, and E Gonzalez The role of nitric oxide on matrix metalloproteinase 2 (MMP2) and MMP9 in placenta and fetus from diabetic rats Reproduction, October 1, 2007; 134(4): 605 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Miettinen, J. Ustinov, P. Ormio, R. Gao, J. Palgi, E. Hakonen, L. Juntti-Berggren, P.-O. Berggren, and T. Otonkoski Downregulation of EGF Receptor Signaling in Pancreatic Islets Causes Diabetes Due to Impaired Postnatal {beta}-Cell Growth Diabetes, December 1, 2006; 55(12): 3299 - 3308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Petri, J. Ahnfelt-Ronne, K. S. Frederiksen, D. G. Edwards, D. Madsen, P. Serup, J. Fleckner, and R S. Heller The effect of neurogenin3 deficiency on pancreatic gene expression in embryonic mice. J. Mol. Endocrinol., October 1, 2006; 37(2): 301 - 316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. B. Geutskens, T. Otonkoski, M-A. Pulkkinen, H. A. Drexhage, and P. J. M. Leenen Macrophages in the murine pancreas and their involvement in fetal endocrine development in vitro J. Leukoc. Biol., October 1, 2005; 78(4): 845 - 852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. L. Suarez-Pinzon, Y. Yan, R. Power, S. J. Brand, and A. Rabinovitch Combination Therapy With Epidermal Growth Factor and Gastrin Increases {beta}-Cell Mass and Reverses Hyperglycemia in Diabetic NOD Mice Diabetes, September 1, 2005; 54(9): 2596 - 2601. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-P. Zhou, A. Madjidi, M. E. Wilson, D. A. Nothhelfer, J. H. Johnson, J. F. Palma, A. Schweitzer, C. Burant, J. E. Blume, and J. D. Johnson Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats Diabetes, September 1, 2005; 54(9): 2612 - 2619. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Roccisana, V. Reddy, R. C. Vasavada, J. A. Gonzalez-Pertusa, M. A. Magnuson, and A. Garcia-Ocana Targeted Inactivation of Hepatocyte Growth Factor Receptor c-met in {beta}-Cells Leads to Defective Insulin Secretion and GLUT-2 Downregulation Without Alteration of {beta}-Cell Mass Diabetes, July 1, 2005; 54(7): 2090 - 2102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. L. Suarez-Pinzon, J. R. T. Lakey, S. J. Brand, and A. Rabinovitch Combination Therapy with Epidermal Growth Factor and Gastrin Induces Neogenesis of Human Islet {beta}-Cells from Pancreatic Duct Cells and an Increase in Functional {beta}-Cell Mass J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3401 - 3409. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A G Kayali, A Stotland, K V Gunst, M Kritzik, G Liu, S Dabernat, Y-Q Zhang, W Wu, and N Sarvetnick Growth factor-induced signaling of the pancreatic epithelium J. Endocrinol., April 1, 2005; 185(1): 45 - 56. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Perez, D. A. Cano, T. Dao-Pick, J.-P. Rougier, Z. Werb, and M. Hebrok Matrix Metalloproteinases 2 and 9 Are Dispensable for Pancreatic Islet Formation and Function In Vivo Diabetes, March 1, 2005; 54(3): 694 - 701. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Suzuki, H. Nakauchi, and H. Taniguchi Prospective Isolation of Multipotent Pancreatic Progenitors Using Flow-Cytometric Cell Sorting Diabetes, August 1, 2004; 53(8): 2143 - 2152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Rachdi, J.-C. Marie, and R. Scharfmann Role for VPAC2 Receptor-Mediated Signals in Pancreas Development Diabetes, January 1, 2003; 52(1): 85 - 92. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Buteau, S. Foisy, E. Joly, and M. Prentki Glucagon-Like Peptide 1 Induces Pancreatic {beta}-Cell Proliferation Via Transactivation of the Epidermal Growth Factor Receptor Diabetes, January 1, 2003; 52(1): 124 - 132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-A. Huotari, P. J. Miettinen, J. Palgi, T. Koivisto, J. Ustinov, D. Harari, Y. Yarden, and T. Otonkoski ErbB Signaling Regulates Lineage Determination of Developing Pancreatic Islet Cells in Embryonic Organ Culture Endocrinology, November 1, 2002; 143(11): 4437 - 4446. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. L. Peghini, M. Iwamoto, M. Raffeld, Y.-J. Chen, S. U. Goebel, J. Serrano, and R. T. Jensen Overexpression of Epidermal Growth Factor and Hepatocyte Growth Factor Receptors in a Proportion of Gastrinomas Correlates with Aggressive Growth and Lower Curability Clin. Cancer Res., July 1, 2002; 8(7): 2273 - 2285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Bernal-Mizrachi, W. Wen, S. Srinivasan, A. Klenk, D. Cohen, and M. A. Permutt Activation of Elk-1, an Ets transcription factor, by glucose and EGF treatment of insulinoma cells Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1286 - E1299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Caric, H. Raphael, J. Viti, A. Feathers, D. Wancio, and L. Lillien EGFRs mediate chemotactic migration in the developing telencephalon Development, November 1, 2001; 128(21): 4203 - 4216. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Rachdi, L. El Ghazi, F. Bernex, J.-J. Panthier, P. Czernichow, and R. Scharfmann Expression of the Receptor Tyrosine Kinase KIT in Mature {beta}-Cells and in the Pancreas in Development Diabetes, September 1, 2001; 50(9): 2021 - 2028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Cras-Meneur, L. Elghazi, P. Czernichow, and R. Scharfmann Epidermal Growth Factor Increases Undifferentiated Pancreatic Embryonic Cells In Vitro: A Balance Between Proliferation and Differentiation Diabetes, July 1, 2001; 50(7): 1571 - 1579. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Kim and M. Hebrok Intercellular signals regulating pancreas development and function Genes & Dev., January 15, 2001; 15(2): 111 - 127. [Full Text]
|
|
|
|
|
|
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]
|
|
