Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen N 2200, Denmark.
Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Dev Cell. 2020 Mar 23;52(6):731-747.e8. doi: 10.1016/j.devcel.2020.01.015. Epub 2020 Feb 13.
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.
Notch 信号通路控制多能胰腺祖细胞（MPCs）的增殖及其向双能祖细胞（BPs）和单能前腺泡细胞（PACs）的分化。在这里，我们表明配体 Dll1 和转录效应因子 Hes1 的快速超短周期振荡对于 MPC 的扩增至关重要，并且 Hes1 振荡参数的变化与 BP 或 PAC 命运的选择性采用有关。相反，Jag1 是一种均匀表达的配体，抑制 MPC 的生长。然而，当 Jag1 的表达后来分离到 PACs 中时，Jag1 对于除最接近的 BP 之外的所有 BP 的特化变得至关重要，并且在 Jag1;Dll1 双突变体中完全丢失了 BP。从解剖学上看，Jag1 突变体的导管形态发生和器官结构在后期之前很少受到干扰，此时导管重塑失败，出现腺泡到导管化生的迹象。因此，我们的研究揭示了发育中的胰腺中由 Jag1 调节的振荡性 Notch 活性对于协调 MPC 的生长和命运是必需的。
