Nakano Yasuhiro, Negishi Naoko, Gocho Seiho, Mine Tetsuya, Sakurai Yuri, Yazawa Masaki, Abe Koichiro, Yagita Hideo, Habu Sonoko, Kageyama Ryoichiro, Kawaguchi Yoshiya, Hozumi Katsuto
Department of Immunology and Research Center for Regenerative Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, 259-1193, Japan.
Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Genes Cells. 2015 Jun;20(6):500-11. doi: 10.1111/gtc.12243. Epub 2015 Apr 27.
Notch signaling has been shown to contribute to murine pancreatic development at various stages. Delta-like 1 (Dll1) or Jagged1 (Jag1) are the Notch ligands that solely function to trigger this signaling during the pancreatic bud stage (~e9.5) or after birth, respectively. However, it has not been elucidated whether these Notch ligands are required at the later stage (e10.5-18.5) when the particular pancreas structures form. Here, we detected the dual expression of Dll1 and Jag1 in the epithelium after e10.5, which was restricted to the ductal cell lineage, including centroacinar cells expressing Sox9, CD133 and Hes1 but not the ductal cell markers Hnf1β and DBA, at e18.5. To evaluate the significance of the Notch ligands during this period, we established double-floxed mice of Dll1 and Jag1 genes with Ptf1a-Cre knock-in allele and examined the effects on development. The abrogation of both ligands but not a single one led to the loss of centroacinar cells, which was due to the decrease in cell proliferation and the increase in cell death, as well as to the reduction of Sox9. These results suggested that Dll1 and Jag1 function redundantly and are necessary to maintain the centroacinar cells as an environmental niche in the developing pancreas.
Notch信号通路已被证明在小鼠胰腺发育的各个阶段都发挥作用。Delta样1（Dll1）或Jagged1（Jag1）是Notch配体，分别在胰腺芽阶段（约胚胎第9.5天）或出生后单独发挥作用来触发该信号通路。然而，在特定胰腺结构形成的后期阶段（胚胎第10.5 - 18.5天），这些Notch配体是否是必需的尚未阐明。在这里，我们检测到胚胎第10.5天后Dll1和Jag1在上皮细胞中的双重表达，这种表达在胚胎第18.5天时局限于导管细胞谱系，包括表达Sox9、CD133和Hes1但不表达导管细胞标志物Hnf1β和DBA的腺泡中心细胞。为了评估这一时期Notch配体的重要性，我们构建了带有Ptf1a - Cre敲入等位基因的Dll1和Jag1基因双敲除小鼠，并研究了其对发育的影响。两种配体的缺失而非单一配体的缺失导致腺泡中心细胞的丢失，这是由于细胞增殖减少、细胞死亡增加以及Sox9表达降低所致。这些结果表明，Dll1和Jag1发挥冗余功能，对于维持发育中的胰腺中作为生态位的腺泡中心细胞是必需的。
