PT - JOURNAL ARTICLE AU - Philip A. Seymour AU - Caitlin A. Collin AU - Mette C. Jørgensen AU - Itaru Imayoshi AU - Kristian H. de Lichtenberg AU - Raphael Kopan AU - Ryoichiro Kageyama AU - Palle Serup TI - Jag1 coordinates release from multipotency with cell fate choice in the developing pancreas AID - 10.1101/336529 DP - 2019 Jan 01 TA - bioRxiv PG - 336529 4099 - http://biorxiv.org/content/early/2019/03/08/336529.short 4100 - http://biorxiv.org/content/early/2019/03/08/336529.full AB - Notch signaling governs the proliferation of multipotent pancreatic progenitor cells (MPCs) and their segregation into proximal duct/endocrine bipotent progenitors (BPs), and distal unipotent pro-acinar cells (PACs). However, it is unclear which ligands are involved and when they act. Here we show antagonistic effects of Jag1 and Dll1 on MPC proliferation. Furthermore, blocking Notch signaling before E13 shunts MPCs into the distal PAC fate, while later inactivation shunts BPs to endocrine differentiation. All BPs are eliminated in Jag1, Dll1 double mutants, with Jag1 expression in PACs proving critical for specification all but the most proximal 5% of BPs. Hes1 expression is elevated in E12.5 Jag1 mutant pancreas and release from the multipotent state is delayed. However, by E14.5 Hes1 expression becomes attenuated, coincident with the biased adoption of a PAC fate. Remarkably, ductal morphogenesis and organ architecture are minimally perturbed in the absence of Jag1 until later stages, when ductal remodeling fails and signs of acinar-to-ductal metaplasia appear. Our study uncovers that an interplay between Jag1 and Dll1 control the multipotent state and that they together specify the entire pancreatic duct cell lineage.