Endoderm development in Caenorhabditis elegans: the synergistic action of ELT-2 and -7 mediates the specification→differentiation transition.
Endoderm development in Caenorhabditis elegans: the synergistic action of ELT-2 and -7 mediates the specification→differentiation transition.
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DOI：
10.1016/j.ydbio.2010.08.020
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发表时间：
2010-11-01
影响因子：
2.7
通讯作者：
Rothman JH
中科院分区：
文献类型：
--
作者：
Sommermann EM;Strohmaier KR;Maduro MF;Rothman JH
从细胞身份的特化到细胞分化成适当和持久的状态的转变对胚胎的发育至关重要。转录谱分析在C.线虫揭示了大量在完全分化的肠中表达的基因;然而，没有发现一旦内胚层被指定就启动它们的表达所必需的调节因子。这些肠道表达的基因具有优势的加塔因子结合位点，并且一种加塔因子ELT-2基于其仅在发育和分化的肠道中的持续表达及其结合这些调控位点的能力而满足这些基因的关键调控因子的预期特征。然而，elt-2（0）敲除突变体的一个显著特征是，虽然它们在孵化后不久由于肠道通道受阻而死亡，但它们仍然含有经历了完全形态分化的肠道。我们发现了第二种肠道特异性加塔因子ELT-7，它与ELT-2深度协同作用，产生对肠道细胞分化至关重要的转录开关。ELT-7首先在早期内胚层谱系中表达，并且当异位表达时，足以激活非内胚层祖细胞中的肠道分化。elt-7被多余的内胚层特异性因子END-1和END-3转录激活，其产物反过来激活其自身的表达和elt-2的表达，构成明显的正反馈系统。虽然elt-7功能丧失突变体缺乏可辨别的表型，但elt-7和elt-2两者的同时丧失导致对具有区域特异性偏倚的肠细胞群的形态分化的显著的全或无阻断，以及减少或消除了许多终末分化基因的肠特异性表达。ELT-2和ELT-7不仅在基因表达的激活中协同作用，而且在通常在瓣膜细胞中表达的基因的抑制中协同作用，所述瓣膜细胞紧邻肠管末端的侧翼。我们的研究结果指出了一种发展策略，即两个协同作用的调节因子之间的正反馈和交叉调节相互作用促进了特定内胚层祖细胞向肠分化程序的决定性和持久性过渡。
The transition from specification of cell identity to the differentiation of cells into an appropriate and enduring state is critical to the development of embryos. Transcriptional profiling in C. elegans has revealed a large number of genes that are expressed in the fully differentiated intestine; however, no regulatory factor has been found to be essential to initiate their expression once the endoderm has been specified. These gut-expressed genes possess a preponderance of GATA factor binding sites and one GATA factor, ELT-2, fulfills the expected characteristics of a key regulator of these genes based on its persistent expression exclusively in the developing and differentiated intestine and its ability to bind these regulatory sites. However, a striking characteristic of elt-2(0) knockout mutants is that while they die shortly after hatching owing to an obstructed gut passage, they nevertheless contain a gut that has undergone complete morphological differentiation. We have discovered a second gut-specific GATA factor, ELT-7, that profoundly synergizes with ELT-2 to create a transcriptional switch essential for gut cell differentiation. ELT-7 is first expressed in the early endoderm lineage and, when expressed ectopically, is sufficient to activate gut differentiation in non-endodermal progenitors. elt-7 is transcriptionally activated by the redundant endoderm-specifying factors END-1 and -3, and its product in turn activates both its own expression and that of elt-2, constituting an apparent positive feedback system. While elt-7 loss-of-function mutants lack a discernible phenotype, simultaneous loss of both elt-7 and elt-2 results in a striking all-or-none block to morphological differentiation of groups of gut cells with a region-specific bias, as well as reduced or abolished gut-specific expression of a number of terminal differentiation genes. ELT-2 and -7 synergize not only in activation of gene expression but also in repression of a gene that is normally expressed in the valve cells, which immediately flank the termini of the gut tube. Our results point to a developmental strategy whereby positive feedback and cross-regulatory interactions between two synergistically acting regulatory factors promote a decisive and persistent transition of specified endoderm progenitors into the program of intestinal differentiation.
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