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Ectopic pancreas is a developmental anomaly occasionally found in humans. Hes1, a main effector of Notch signaling, regulates the fate and differentiation of many cell types during development. To gain insights into the role of the Notch pathway in pancreatic fate determination, we combined the use of Hes1-knockout mice and lineage tracing employing the Cre/loxP system to specifically mark pancreatic precursor cells and their progeny in Ptf1a-cre and Rosa26 reporter mice. We show that inactivation of Hes1 induces misexpression of Ptf1a in discrete regions of the primitive stomach and duodenum and throughout the common bile duct. All ectopic Ptf1a-expressing cells were reprogrammed, or transcommitted, to multipotent pancreatic progenitor status and subsequently differentiated into mature pancreatic exocrine, endocrine, and duct cells. This process recapitulated normal pancreatogenesis in terms of morphological and genetic features. Furthermore, analysis of Hes1/Ptf1a double mutants revealed that ectopic Ptf1a-cre lineage-labeled cells adopted the fate of region-appropriate gut epithelium or endocrine cells similarly to Ptf1a-inactivated cells in the native pancreatic buds. Our data demonstrate that the Hes1-mediated Notch pathway is required for region-appropriate specification of pancreas in the developing foregut endoderm through regulation of Ptf1a expression, providing novel insight into the pathogenesis of ectopic pancreas development in a mouse model.
Neoplasia is an unusual complication of Meckel diverticulum. Most tumors of Meckel diverticulum are neuroendocrine or mesenchymal in origin. Adenocarcinomas represent a minority of the tumors that arise in Meckel diverticulum and are generally thought to develop from either endogenous small intestinal epithelium or heterotopic gastric epithelium. Despite the presence of ectopic pancreas in a small fraction of Meckel diverticula, convincing evidence of tumors that arise from heterotopic pancreatic exocrine tissue has not been described in this setting. Intraductal papillary mucinous neoplasms are relatively uncommon tumors of pancreatic ductal epithelial cells that line the main pancreatic duct or its major side branches. We present an unusual case of an intraductal papillary mucinous neoplasm that arose in a heterotopic pancreas within a Meckel diverticulum.