Lipophilic regulator of a developmental switch in Caenorhabditis elegans
Lipophilic regulator of a developmental switch in Caenorhabditis elegans
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DOI：
10.1111/j.1474-9728.2004.00126.x
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发表时间：
2004-12-01
期刊：
影响因子：
7.8
通讯作者：
Lithgow, GJ
中科院分区：
文献类型：
--
作者：
Gill, MS;Held, JM;Lithgow, GJ
在秀丽线虫中，发育成生殖性成虫或作为达尔幼虫停止发育的决定受到多种途径的影响，包括胰岛素样和转化生长因子β(TGFβ)样的信号通路。有人提出，亲脂激素作用于这些途径的下游，以调节Dauer的形成。这种激素的一个可能靶点是DAF-12，一种孤儿核激素受体，它介导这些发育决定，也影响成年人的寿命。为了寻找亲脂激素，我们从线虫的大规模培养中产生了亲脂提取物，并表明它们拯救了Dauer组成表型的1daf-2胰岛素信号突变体和TGFbeta信号突变体daf-7。这些提取物也能够挽救daf-9突变体的致命Dauer表型，这些突变体缺乏被认为参与DAF-12配体合成的P450类固醇羟基酶；然而，提取物对被预测为配体不敏感的DAF-12配体结合结构域突变体没有影响。这种激素的产生似乎依赖于DAF-9，因为DAF-9的提取物；DAF-12双突变体不表现出这种活性。亲脂提取物的初步分级表明，其活性是疏水的，具有一些极性性质，与一种小的亲脂激素相一致。我们认为DAF-9通过DAF-12起作用，是DAF-9合成的一种激素。
In Caenorhabditis elegans, the decision to develop into a reproductive adult or arrest as a dauer larva is influenced by multiple pathways including insulin-like and transforming growth factor beta (TGFbeta)-like signalling pathways. It has been proposed that lipophilic hormones act downstream of these pathways to regulate dauer formation. One likely target for such a hormone is DAF-12, an orphan nuclear hormone receptor that mediates these developmental decisions and also influences adult lifespan. In order to find lipophilic hormones we have generated lipophilic extracts from mass cultures of C elegans and shown that they rescue the dauer constitutive phenotype of class 1 daf-2 insulin signalling mutants and the TGFbeta signalling mutant daf-7. These extracts are also able to rescue the lethal dauer phenotype of daf-9 mutants, which lack a P450 steroid hydroxylase thought to be involved in the synthesis of the DAF-12 ligand; extracts, however, have no effect on a DAF-12 ligand binding domain mutant that is predicted to be ligand insensitive. The production of this hormone appears to be DAF-9 dependent as extracts from a daf-9;daf-12 double mutant do not exhibit this activity. Preliminary fractionation of the lipophilic extracts shows that the activity is hydrophobic with some polar properties, consistent with a small lipophilic hormone. We propose that the dauer rescuing activity is a hormone synthesized by DAF-9 that acts through DAF-12.