Jagged1 in pancreatic endocrine and duct development

The pancreas consists of both endocrine and exocrine tissue. The endocrine cells are contained within the islets of Langerhans and contribute to the regulation of blood glucose homeostasis. The exocrine tissue contains both acinar cells and ducts; it secretes digestive enzymes into the duodenum. The Notch signaling pathway is known to contribute to pancreas development, but the role of individual components is not well defined. To determine how the Notch ligand Jagged1 (Jag1) functions during pancreas development, we deleted Jag1 in the foregut endoderm with the Foxa3-Cre transgene. Postnatal Jag1 mutants demonstrate the expected Notch pathway phenotype, with increased Ngn3 expression, α-cell mass, and endocrine cell percentage. However, in sharp contrast to postnatal animals, Jag1-deficient embryos display increased expression of Notch transcriptional targets and decreased Ngn3 expression, resulting in reduced endocrine lineage allocation. I demonstrate that expression of the Notch modifier Manic Fringe (Mfng) is limited to endocrine precursors and suggest that Delta-like 1 (Dll1) signaling is inhibited by Jag1 when Notch is glycosylated, providing an explanation for the paradoxical inhibition of Notch signaling by Jag1 during mid-gestation embryonic pancreas development. Around 20% of the Jag1 loxP/loxP; Foxa3-Cre also had an exocrine phenotype, with enlarged ducts and fatty replacement of the acinar tissue. Because the Foxa3-Cre transgene is mosaic and Jag1loxP/loxP; Foxa3-Cre+ mice displayed a variable phenotype, we deleted Jag1 in the pancreas using Pdx1-Cre. 80% of these mice had the fatty replacement phenotype we had previously observed. This phenotype is probably the result of ductal malformation in Jag1 mutants