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J. Cell Biol.,
Volume 140, Number 6, March 23, 1998 1519-1534
* The Islet Research Laboratory at The Whittier Institute for Diabetes, Department of Pediatrics, ¶ The National Center for
Microscopy and Imaging Research, University of California San Diego, La Jolla, California 92037; Cell adhesion molecules (CAMs) are important mediators of cell-cell interactions and regulate cell
fate determination by influencing growth, differentiation, and organization within tissues. The human pancarcinoma antigen KSA is a glycoprotein of 40 kD originally identified as a marker of rapidly proliferating
tumors of epithelial origin. Interestingly, most normal
epithelia also express this antigen, although at lower
levels, suggesting that a dynamic regulation of KSA
may occur during cell growth and differentiation. Recently, evidence has been provided that this glycoprotein may function as an epithelial cell adhesion molecule (Ep-CAM). Here, we report that Ep-CAM
exhibits the features of a morphoregulatory molecule involved in the development of human pancreatic islets.
We demonstrate that Ep-CAM expression is targeted
to the lateral domain of epithelial cells of the human fetal pancreas, and that it mediates calcium-independent cell-cell adhesion. Quantitative confocal immunofluorescence in fetal pancreata identified the highest levels
of Ep-CAM expression in developing islet-like cell
clusters budding from the ductal epithelium, a cell compartment thought to comprise endocrine progenitors. A
surprisingly reversed pattern was observed in the human adult pancreas, displaying low levels of Ep-CAM
in islet cells and high levels in ducts. We further demonstrate that culture conditions promoting epithelial cell
growth induce upregulation of Ep-CAM, whereas endocrine differentiation of fetal pancreatic epithelial cells, transplanted in nude mice, is associated with a
downregulation of Ep-CAM expression. In addition, a
blockade of Ep-CAM function by KS1/4 mAb induced
insulin and glucagon gene transcription and translation
in fetal pancreatic cell clusters. These results indicate that developmentally regulated expression and function of Ep-CAM play a morphoregulatory role in pancreatic islet ontogeny.
Department of Molecular
and Experimental Medicine, and ** Department of Immunology, The Scripps Research Institute, La Jolla, California 92037; The
Diabetes Research Institute, University of Miami School of Medicine, Miami, Florida 33136; and § Brookdale Center for
Molecular Biology, The Mount Sinai School of Medicine, New York 10029
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