Sustained Notch signaling in progenitors is required for sequential emergence of distinct cell lineages during organogenesis
Sustained Notch signaling in progenitors is required for sequential emergence of distinct cell lineages during organogenesis
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DOI：
10.1101/gad.1444706
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发表时间：
2006-10-01
影响因子：
10.5
通讯作者：
Rosenfeld, Michael G.
中科院分区：
文献类型：
--
作者：
Zhu, Xiaoyan;Zhang, Jie;Rosenfeld, Michael G.
哺乳动物器官发生的结果是祖细胞中信号通路的协同作用，这些信号通路诱导了对器官和细胞类型确定至关重要的一系列受调控的转录因子。在这里，我们证明了持续的Notch活性对于特定的增殖祖细胞群的暂时维持是必需的，这是在垂体器官发生过程中确定晚起细胞谱系的能力的基础。编码Notch途径主要介质的RBP-J的条件性缺失导致祖细胞过早分化，基本螺旋-环-螺旋(BHLH)因子Hes1的缺失重现了这种表型，以及晚期(Pit1)谱系向早期(皮质激素)谱系的转换。Noch信号是维持组织特异性配对样同源域转录因子Prop1的表达所必需的，而Prop1是生成Pit1谱系所必需的。在有丝分裂后的Pit1(+)细胞中，Notch信号的减弱是终末分化所必需的，而Notch抑制的Pit1靶基因Math3是产生GH的生长激素成熟和增殖所必需的。因此，在前体细胞中持续的Notch信号是必要的，以防止后期出现的细胞谱系转变为早期出生的细胞谱系，从而允许指定不同的细胞类型，这一策略很可能在哺乳动物器官发生中被广泛使用。
Mammalian organogenesis results from the concerted actions of signaling pathways in progenitor cells that induce a hierarchy of regulated transcription factors critical for organ and cell type determination. Here we demonstrate that sustained Notch activity is required for the temporal maintenance of specific cohorts of proliferating progenitors, which underlies the ability to specify late-arising cell lineages during pituitary organogenesis. Conditional deletion of Rbp-J, which encodes the major mediator of the Notch pathway, leads to premature differentiation of progenitor cells, a phenotype recapitulated by loss of the basic helix-loop-helix (bHLH) factor Hes1, as well as a conversion of the late (Pit1) lineage into the early (corticotrope) lineage. Notch signaling is required for maintaining expression of the tissue-specific paired-like homeodomain transcription factor, Prop1, which is required for generation of the Pit1 lineage. Attenuation of Notch signaling is necessary for terminal differentiation in post-mitotic Pit1(+) cells, and the Notch-repressed Pit1 target gene, Math3, is specifically required for maturation and proliferation of the GH-producing somatotrope. Thus, sustained Notch signaling in progenitor cells is required to prevent conversion of the late-arising cell lineages to early-born cell lineages, permitting specification of diverse cell types, a strategy likely to be widely used in mammalian organogenesis.