Bodofsky Shari, Liberatore Katarina, Pioppo Lauren, Lapadula Dominic, Thompson Lily, Birnbaum Susanna, McClung George, Kartik Akshara, Clever Sheila, Wightman Bruce
Biology Department, Muhlenberg College, Allentown, PA, 18104, USA.
Gene Expr Patterns. 2018 Dec;30:71-81. doi: 10.1016/j.gep.2018.10.003. Epub 2018 Nov 4.
The nhr-67 nuclear receptor gene of Caenorhabditis elegans encodes the ortholog of the Drosophila tailless and vertebrate Tlx genes. In C. elegans, nhr-67 plays multiple roles in the development of the uterus during L2 and L3 larval stages. Four pre-VU cells are born in the L2 stage and form the precursor complement for the ventral surface of the mature uterus. One of the four pre-VU cells becomes the anchor cell (AC), which exits the cell cycle and differentiates, while the remaining three VU cells serve as stem cells that populate the ventral uterus. The nhr-67 gene functions in the development of both VU cell lineages and AC differentiation. Hypomorphic mutations in nhr-67 identify a 276bp region of the distal promoter that is sufficient to activate nhr-67 expression in pre-VU cells and the AC. The 276bp region includes 8 conserved potential cis-acting sites, including two E boxes and a nuclear receptor binding site. Mutational analysis demonstrates that the two E boxes are required for expression of nhr-67 in uterine precursor cells. The E/daughterless ortholog HLH-2 binds these sites as a homodimer, thus playing a central role in activating nhr-67 expression in the uterine precursors. At least two other binding activities, one of which may be the nhr-25/Ftz-F1 nuclear receptor transcription factor, also contribute to uterine precursor cell expression. The organization of the nhr-67 uterine precursor enhancer is compared to similar conserved enhancers in the egl-43, lag-2, and lin-3 genes, which contain the same HLH-2-binding E boxes and are similarly expressed in both pre-VU cells and the AC. This basic regulatory module allows the coordinated expression of at least four genes. Expression of genes in different cells that must coordinate to form a mature organ is driven by a shared set of promoter elements, which integrate multiple transcription factor inputs.
秀丽隐杆线虫的nhr - 67核受体基因编码果蝇无尾基因和脊椎动物Tlx基因的直系同源基因。在秀丽隐杆线虫中，nhr - 67在L2和L3幼虫阶段子宫发育过程中发挥多种作用。四个前VU细胞在L2阶段产生，形成成熟子宫腹面的前体细胞补充。四个前VU细胞中的一个成为锚定细胞（AC），它退出细胞周期并分化，而其余三个VU细胞作为填充腹侧子宫的干细胞。nhr - 67基因在VU细胞谱系发育和AC分化中起作用。nhr - 67的亚效突变确定了远端启动子的一个276bp区域，该区域足以激活前VU细胞和AC中nhr - 67的表达。276bp区域包括8个保守的潜在顺式作用位点，包括两个E盒和一个核受体结合位点。突变分析表明，两个E盒是子宫前体细胞中nhr - 67表达所必需的。E/无女儿直系同源基因HLH - 2作为同二聚体结合这些位点，因此在激活子宫前体细胞中nhr - 67的表达中起核心作用。至少还有另外两种结合活性，其中一种可能是nhr - 25/Ftz - F1核受体转录因子，也有助于子宫前体细胞的表达。将nhr - 67子宫前体增强子的组织与egl - 43、lag - 2和lin - 3基因中类似的保守增强子进行比较，这些基因包含相同的HLH - 2结合E盒，并且在前VU细胞和AC中表达相似。这个基本的调控模块允许至少四个基因的协调表达。不同细胞中必须协调以形成成熟器官的基因表达由一组共享的启动子元件驱动，这些元件整合了多种转录因子输入。
