Cras-Méneur Corentin, Conlon Megan, Zhang Yaqing, Pasca Di Magliano Marina, Bernal-Mizrachi Ernesto
University of Michigan in Ann Arbor, Internal Medicine Department, MEND Division Brehm Tower, 1000 Wall St, Ann Arbor, MI 48105-1912, USA.
University of Michigan in Ann Arbor, Department of Surgery, General Surgery Division 4304 Cancer Center, 1500 E. Medical Center Drive, Ann Arbor MI 48109-5936, USA.
Sci Rep. 2016 May 31;6:26874. doi: 10.1038/srep26874.
Notch signaling is known to control early pancreatic differentiation through Ngn3 repression. In later stages, downstream of Notch, the Presenilins are still required to maintain the endocrine fate allocation. Amongst their multiple targets, it remains unclear which one actually controls the maintenance of the fate of the early islets. Conditional deletions of the Notch effector RBP-Jκ with lineage tracing in Presenilin-deficient endocrine progenitors, demonstrated that this factor is central to the control of the fate through a non-canonical Notch mechanism. RBP-Jκ mice exhibit normal islet morphogenesis and function, however, a fraction of the progenitors fails to differentiate and develop into disorganized masses resembling acinar to ductal metaplasia and chronic pancreatitis. A subsequent deletion of RBP-Jκ in forming β-cells led to the transdifferentiation into the other endocrine cells types, indicating that this factor still mediates the maintenance of the fate within the endocrine lineage itself. These results highlight the dual importance of Notch signaling for the endocrine lineage. Even after Ngn3 expression, Notch activity is required to maintain both fate and maturation of the Ngn3 progenitors. In a subset of the cells, these alterations of Notch signaling halt their differentiation and leads to acinar to ductal metaplasia.
已知Notch信号通过抑制Ngn3来控制胰腺早期分化。在后期，Notch下游的早老素对于维持内分泌命运分配仍然是必需的。在它们的多个靶点中，究竟哪个靶点实际上控制着早期胰岛命运的维持仍不清楚。在早老素缺陷的内分泌祖细胞中通过谱系追踪对Notch效应因子RBP-Jκ进行条件性缺失，结果表明该因子对于通过非经典Notch机制控制命运至关重要。RBP-Jκ基因敲除小鼠表现出正常的胰岛形态发生和功能，然而，一部分祖细胞无法分化并发展为类似于腺泡到导管化生和慢性胰腺炎的杂乱团块。随后在正在形成的β细胞中删除RBP-Jκ导致其转分化为其他内分泌细胞类型，这表明该因子仍然介导内分泌谱系内命运的维持。这些结果突出了Notch信号对于内分泌谱系的双重重要性。即使在Ngn3表达之后，Notch活性对于维持Ngn3祖细胞的命运和成熟也是必需的。在一部分细胞中，Notch信号的这些改变会阻止它们的分化并导致腺泡到导管化生。
