Notch-mediated patterning and cell fate allocation of pancreatic progenitor cells
Notch-mediated patterning and cell fate allocation of pancreatic progenitor cells
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DOI：
10.1242/dev.075804
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发表时间：
2012-05-15
期刊：
影响因子：
4.6
通讯作者：
Jensen, Jan
中科院分区：
文献类型：
--
作者：
Afelik, Solomon;Qu, Xiaoling;Jensen, Jan
早期胰腺形态发生的特征在于胰腺祖细胞的未定型池转化成由“尖端”和“躯干”结构域组成的分支胰腺上皮。这些结构域具有不同的分子特征并分化成不同的胰腺细胞谱系。上皮分支尖端的细胞发育成腺泡细胞，而躯干亚室的细胞分化成内分泌细胞和导管细胞。最近的遗传分析强调了关键的转录调节因子在这些亚室的规范中的作用。在这里，我们分析了在小鼠中的作用，Notch信号在多能胰腺祖细胞的图案，通过镶嵌过度表达的Notch信号拮抗剂，显性负主谋样1，导致野生型和Notch抑制胰腺祖细胞的混合物。我们发现Notch信号的减弱在终末分化之前对多能胰腺祖细胞具有明显的模式化作用。相对于野生型细胞，Notch抑制的细胞失去主干标记基因并获得尖端标记基因的表达。Notch抑制的细胞随后分化成腺泡细胞，而导管和内分泌群体主要由野生型细胞形成。从机制上讲，这些观察结果可以解释为表达的树干决定基因Nkx6.1的Notch的要求。这得到了RBP-1与Nkx6.1近端启动子直接结合的发现的支持。
Early pancreatic morphogenesis is characterized by the transformation of an uncommitted pool of pancreatic progenitor cells into a branched pancreatic epithelium that consists of 'tip' and 'trunk' domains. These domains have distinct molecular signatures and differentiate into distinct pancreatic cell lineages. Cells at the branched tips of the epithelium develop into acinar cells, whereas cells in the trunk subcompartment differentiate into endocrine and duct cells. Recent genetic analyses have highlighted the role of key transcriptional regulators in the specification of these subcompartments. Here, we analyzed in mice the role of Notch signaling in the patterning of multipotent pancreatic progenitor cells through mosaic overexpression of a Notch signaling antagonist, dominant-negative mastermind-like 1, resulting in a mixture of wild-type and Notch-suppressed pancreatic progenitor cells. We find that attenuation of Notch signaling has pronounced patterning effects on multipotent pancreatic progenitor cells prior to terminal differentiation. Relative to the wild-type cells, the Notch-suppressed cells lose trunk marker genes and gain expression of tip marker genes. The Notch-suppressed cells subsequently differentiate into acinar cells, whereas duct and endocrine populations are formed predominantly from the wild-type cells. Mechanistically, these observations could be explained by a requirement of Notch for the expression of the trunk determination gene Nkx6.1. This was supported by the finding of direct binding of RBP-j. to the Nkx6.1 proximal promoter.