Conditional ablation of Notch signaling in pancreatic development
Conditional ablation of Notch signaling in pancreatic development
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DOI：
10.1242/dev.013722
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发表时间：
2008-08-15
期刊：
影响因子：
4.6
通讯作者：
Schmid, Roland M.
中科院分区：
文献类型：
--
作者：
Nakhai, Hassan;Siveke, Jens T.;Schmid, Roland M.
Notch信号成员Notch1、Notch2和Rbpj在外分泌胰腺发育中的作用尚未明确。因此，我们使用Ptf1a（+/Cre(ex1)）小鼠与固定Rbpj或Notch1/Notch2小鼠杂交，分析了条件胰脏特异性Rbpj和Notch1/Notch2联合敲除小鼠。对不同胚胎阶段小鼠胰腺外分泌和内分泌发育进行了分析。胰腺祖细胞中Rbpj的缺失导致胚胎18.5天前胰腺外分泌发育受损，并导致胰腺祖细胞过早分化为内分泌细胞。在缺乏Rbpj的胰腺中，表达淀粉酶的腺泡和胰岛在胚胎晚期和出生后发育期间形成，这表明Rbpj在早期而不是晚期发育中起重要作用。与这种严重表型相反，Notch1和Notch2的同时失活仅在早期胚胎发育期间适度干扰胰腺上皮细胞的增殖，而不抑制胰腺发育。我们的研究结果表明，与Rbpj相反，Notch1和Notch2在胰腺发生中不是必需的。这些数据支持Rbpj在外分泌胰腺发育中的notch独立作用。此外，我们的研究结果表明，在胰腺发育晚期，外分泌细胞的分化和维持是独立于Rbpj的。
The role of the Notch signaling members Notch1, Notch2 and Rbpj in exocrine pancreatic development is not well defined. We therefore analyzed conditional pancreas-specific Rbpj and combined Notch1/Notch2 knockout mice using Ptf1a(+/Cre(ex1)) mice crossed with floxed Rbpj or Notch1/Notch2 mice. Mice were analyzed at different embryonic stages for pancreatic exocrine and endocrine development. The absence of Rbpj in pancreatic progenitor cells impaired exocrine pancreas development up to embryonic day 18.5 and led to premature differentiation of pancreatic progenitors into endocrine cells. In Rbpj-deficient pancreata, amylase-expressing acini and islets formed during late embryonic and postnatal development, suggesting an essential role of Rbpj in early but not late development. Contrary to this severe phenotype, the concomitant inactivation of Notch1 and Notch2 only moderately disturbed the proliferation of pancreatic epithelial cells during early embryonic development, and did not inhibit pancreatic development. Our results show that, in contrast to Rbpj, Notch1 and Notch2 are not essential for pancreatogenesis. These data favor a Notch-independent role of Rbpj in the development of the exocrine pancreas. Furthermore, our findings suggest that in late stages of pancreatic development exocrine cell differentiation and maintenance are independent of Rbpj.