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Abstract
Cadherin-mediated cell-cell adhesion plays an important role in organ development and changes in cadherin expression are often linked to morphogenetic and pathogenic events. Cadherins interact with other intracellular components to form adherens junctions (AJs) and provide mechanical attachments between adjacent cells. E-cadherin (Cdh1) represents an integral component of these intercellular junctions. To elucidate the function of E-cadherin in the developing pancreas, we generated and studied pancreas-specific Cdh1-knockout (Cdh1ΔPan/ΔPan) mice. Cdh1ΔPan/ΔPan mice exhibit normal body size at birth, but fail to gain weight and become hypoglycemic soon afterward. We found that E-cadherin is not required for the establishment of apical-basal polarity or pancreatic exocrine cell identity at birth. However, four days after birth, the pancreata of Cdh1ΔPan/ΔPan mutants display progressive deterioration of exocrine architecture and dysregulation of Wnt and YAP signaling. At this time point, the acinar cells of Cdh1ΔPan/ΔPan mutants begin to exhibit ductal phenotypes, suggesting acinar-to-ductal metaplasia (ADM) in the E-cadherin-deficient pancreas. Our findings demonstrate that E-cadherin plays an integral role in the maintenance of exocrine architecture and regulation of homeostatic signaling. The present study provides insights into the involvement of cadherin-mediated cell-cell adhesion in pathogenic conditions such as pancreatitis or pancreatic cancer.
Highlights
Coordinated at the adherens junctions (AJs), and a number of studies have systematically addressed the requirement of normal Wnt and YAP pathway expression during development[15,16]
The adherens junction (AJ) structure has been considered critical to the maintenance of epithelial tissues throughout the body
At AJs, catenins bind to the cytoplasmic domain of E-cadherin, and link cell adhesion complexes to the intracellular actin cytoskeleton[27,28]
Summary
Coordinated at the AJ, and a number of studies have systematically addressed the requirement of normal Wnt and YAP pathway expression during development[15,16]. The roles which individual components of the AJ play in maintaining epithelial homeostasis and preventing pathogenic growth signaling are worthy of further evaluation Despite these pioneer studies deciphering the involvement of AJ components in regulating pancreas development, the role of E-cadherin in the development and maintenance of the pancreas remains elusive. By postnatal day 4 a progressive deterioration of exocrine architecture became apparent, manifesting in significant reductions to both body weight and blood glucose levels, as well as postnatal lethality which can likely be attributed to pancreatic insufficiency Through this time period, cells of the Cdh1ΔPan/ΔPan pancreas were unable to form intercellular adherens junctions (AJs), confirming the requirement of E-cadherin for proper formation of the AJ structure. The present study provides evidence that E-cadherin, aside from playing a prominent role in intercellular adhesion, exerts a significant stabilizing effect on pancreas organ homeostasis, and that its inactivation may promote pathogenesis in the pancreas
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