RT Journal Article
SR Electronic
T1 Jag1 modulates an oscillatory Dll1-Notch-Hes1 signaling module to coordinate growth and fate of pancreatic progenitors
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 336529
DO 10.1101/336529
A1 Philip A. Seymour
A1 Caitlin A. Collin
A1 Anuska l. R. Egeskov-Madsen
A1 Mette C. Jørgensen
A1 Hiromi Shimojo
A1 Itaru Imayoshi
A1 Kristian H. de Lichtenberg
A1 Raphael Kopan
A1 Ryoichiro Kageyama
A1 Palle Serup
YR 2019
UL http://biorxiv.org/content/early/2019/06/26/336529.abstract
AB Notch signaling controls proliferation of multipotent pancreatic progenitor cells (MPCs) and their segregation into bipotent progenitors (BPs) and unipotent pro-acinar cells (PACs). Here we uncover fast ultradian oscillations in the ligand Dll1, and the transcriptional effector Hes1, which proved crucial for MPC expansion. Conversely Jag1, a uniformly expressed ligand, curbed MPC growth, but as expression later segregated to PACs it proved critical for specifying all but the most proximal 5% of BPs, while BPs were entirely lost in Jag1, Dll1 double mutants. Moreover, experimentally induced changes in Hes1 oscillation parameters was associated with selective adoption of BP or PAC fates. Anatomically, ductal morphogenesis and organ architecture is minimally perturbed in Jag1 mutants until later stages, when ductal remodeling fails and signs of acinar-to-ductal metaplasia appear. Our study uncovers oscillating Notch activity in the developing pancreas, which along with modulation by Jag1 is required to coordinate MPC growth and fate.