A Genome-Wide RNAi Screen for Enhancers of a Germline Tumor Phenotype Caused by Elevated GLP-1/Notch Signaling in Caenorhabditis elegans.
A Genome-Wide RNAi Screen for Enhancers of a Germline Tumor Phenotype Caused by Elevated GLP-1/Notch Signaling in Caenorhabditis elegans.
复制标题
对秀丽隐杆线虫中 GLP-1/Notch 信号传导升高引起的种系肿瘤表型增强子进行全基因组 RNAi 筛选。
DOI：
10.1534/g3.120.401632
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发表时间：
2020-12-03
期刊：
影响因子：
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通讯作者：
Hubbard EJA
中科院分区：
文献类型：
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作者：
Dalfó D;Ding Y;Liang Q;Fong A;Cipriani PG;Piano F;Zheng JC;Qin Z;Hubbard EJA
干细胞在体内受到严格控制。自我更新和分化之间的平衡以及增殖速率往往受到多种因素的调节。秀丽隐杆线虫雌雄同体种系为研究体内干细胞提供了一个简单且易于使用的系统。在该系统中，GLP-1/Notch 活性可防止远端生殖细胞响应附近远端尖端细胞的配体产生而分化，从而支持干细胞池。然而，种系发育相对于体细胞性腺发育的延迟可能导致未分化的生殖细胞池持续存在，以响应近端体细胞性腺中表达的替代Notch配体。这些未分化的生殖细胞形成近端肿瘤，在成年后会阻塞输卵管。这种类型的“潜在生态位”驱动的近端肿瘤在限制温度下具有温度敏感性弱功能获得性突变glp-1（ar202）的线虫中具有高度渗透性。在允许的温度下，很少有蠕虫会长出肿瘤。然而，一些干预措施提高了在允许温度下近端肿瘤形成的外显率，包括减少胰岛素信号传导或消融最远端鞘细胞。为了系统地识别增强近端肿瘤形成的遗传扰动，我们寻找在RNAi耗尽后，在允许的温度下提高glp-1（ar202）中携带近端种系肿瘤的线虫百分比的基因。我们鉴定了 43 个代表多种功能类别的基因，其中最丰富的是“翻译”。这些基因中的一些也影响远端种系，而一些是保守基因，在该系统中以前不知道这些基因与Notch的遗传相互作用。
Stem cells are tightly controlled in vivo. Both the balance between self-renewal and differentiation and the rate of proliferation are often regulated by multiple factors. The Caenorhabditis elegans hermaphrodite germ line provides a simple and accessible system for studying stem cells in vivo. In this system, GLP-1/Notch activity prevents the differentiation of distal germ cells in response to ligand production from the nearby distal tip cell, thereby supporting a stem cell pool. However, a delay in germline development relative to somatic gonad development can cause a pool of undifferentiated germ cells to persist in response to alternate Notch ligands expressed in the proximal somatic gonad. This pool of undifferentiated germ cells forms a proximal tumor that, in adulthood, blocks the oviduct. This type of “latent niche”-driven proximal tumor is highly penetrant in worms bearing the temperature-sensitive weak gain-of-function mutation glp-1(ar202) at the restrictive temperature. At the permissive temperature, few worms develop tumors. Nevertheless, several interventions elevate the penetrance of proximal tumor formation at the permissive temperature, including reduced insulin signaling or the ablation of distal-most sheath cells. To systematically identify genetic perturbations that enhance proximal tumor formation, we sought genes that, upon RNAi depletion, elevate the percentage of worms bearing proximal germline tumors in glp-1(ar202) at the permissive temperature. We identified 43 genes representing a variety of functional classes, the most enriched of which is “translation”. Some of these genes also influence the distal germ line, and some are conserved genes for which genetic interactions with Notch were not previously known in this system.