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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 EGFR 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 insulinpositive 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.

The presence of epidermal growth factor (EGF) and transforming growth factor-α (TGFα) immunoreactivities in fetal human tissues was studied immunohistochemically at different gestational ages. EGF and TGFαimmunoreactivities were detected from the 20th gestational wk. EGF immunoreactivity was limited to the small intestine, but TGFαimmunoreactive cells were present in the colon also. According to radioreceptor assay, the intestine of a 19-wk-old human fetus contained 10 times more EGF receptor-binding substance than EGF, as measured by immunofluorometric assay. Chromatographic analysis suggests that TGFα-like peptides account for at least part of this activity, as so argues in favor of the presence of TGFα- and EGF-like peptides in the human fetal gut. Whether they are synthesized in the fetus is yet unknown.

ABSTRACT: The presence of epidermal growth factor (EGF) and transforming growth factor-a (TGFa) immunoreactivities in fetal human tissues was studied immunohistochemically at different gestational ages. EGF and TGFaimmunoreactivities were detected from the 20th gestational wk. EGF immunoreactivity was limited to the small intestine, but TGFaimmunoreactive cells were present in the colon also. According to radioreceptor assay, the intestine of a 19-wk-old human fetus contained 10 times more EGF receptor-binding substance than EGF, as measured by immunofluorometric assay. Chromatographic analysis suggests that TGFa-like peptides account for at least part of this activity, as so argues in favor of the presence of TGFa- and EGF-like peptides in the human fetal gut. Whether they are synthesized in the fetus is yet unknown.