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Jag1 Modulates an Oscillatory Dll1-Notch-Hes1 Signaling Module to Coordinate Growth and Fate of Pancreatic Progenitors.
Developmental Cell ( IF 11.8 ) Pub Date : 2020-02-04 , DOI: 10.1016/j.devcel.2020.01.015 Philip Allan Seymour 1 , Caitlin Alexis Collin 1 , Anuska la Rosa Egeskov-Madsen 1 , Mette Christine Jørgensen 1 , Hiromi Shimojo 2 , Itaru Imayoshi 3 , Kristian Honnens de Lichtenberg 1 , Raphael Kopan 4 , Ryoichiro Kageyama 2 , Palle Serup 1
Developmental Cell ( IF 11.8 ) Pub Date : 2020-02-04 , DOI: 10.1016/j.devcel.2020.01.015 Philip Allan Seymour 1 , Caitlin Alexis Collin 1 , Anuska la Rosa Egeskov-Madsen 1 , Mette Christine Jørgensen 1 , Hiromi Shimojo 2 , Itaru Imayoshi 3 , Kristian Honnens de Lichtenberg 1 , Raphael Kopan 4 , Ryoichiro Kageyama 2 , Palle Serup 1
Affiliation
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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 showed that fast ultradian oscillations of the ligand Dll1 and the transcriptional effector Hes1 were crucial for MPC expansion, and changes in Hes1 oscillation parameters were associated with selective adoption of BP or PAC fate. Conversely, Jag1, a uniformly expressed ligand, restrained MPC growth. However, when its expression later segregated to PACs, Jag1 became critical for the specification of all but the most proximal BPs, and BPs were entirely lost in Jag1; Dll1 double mutants. Anatomically, ductal morphogenesis and organ architecture are minimally perturbed in Jag1 mutants until later stages, when ductal remodeling fails, and signs of acinar-to-ductal metaplasia appear. Our study thus uncovers that oscillating Notch activity in the developing pancreas, modulated by Jag1, is required to coordinate MPC growth and fate.
更新日期：2020-02-20
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