Skirball Institute of Biomolecular Medicine, Departments of Cell Biology and Pathology, NYU Grossman School of Medicine.
School of Medicine, Tongji University.
G3 (Bethesda). 2020 Dec 3;10(12):4323-4334. doi: 10.1534/g3.120.401632.
Stem cells are tightly controlled Both the balance between self-renewal and differentiation and the rate of proliferation are often regulated by multiple factors. The hermaphrodite germ line provides a simple and accessible system for studying stem cells 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 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 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.
干细胞受到严密调控。自我更新和分化之间的平衡以及增殖速度通常受到多种因素的调节。雌雄同体的生殖系为研究干细胞提供了一个简单且易于处理的系统。在这个系统中，GLP-1/Notch 活性防止了远端生殖细胞的分化，以响应来自附近远端尖端细胞的配体产生，从而支持干细胞池的存在。然而，生殖系相对于体生殖腺的发育延迟会导致未分化的生殖细胞池在近端体生殖腺中表达的替代 Notch 配体的作用下持续存在。这个未分化的生殖细胞池形成一个近端肿瘤，在成年期会阻塞输卵管。这种类型的“潜伏小生境”驱动的近端肿瘤在携带温度敏感的弱功能获得性突变 在限制温度下具有高度的穿透性。在许可温度下，很少有蠕虫会发展成肿瘤。然而，几种干预措施会提高在许可温度下形成近端肿瘤的穿透性，包括降低胰岛素信号或消融最远端鞘细胞。为了系统地鉴定增强近端肿瘤形成的遗传扰动，我们寻找了在 RNAi 耗尽后，会提高 在许可温度下携带近端生殖系肿瘤的蠕虫百分比的基因。我们鉴定了 43 个代表各种功能类别的基因，其中最丰富的是“翻译”。其中一些基因也会影响远端生殖系，并且其中一些是在这个系统中以前不知道与 Notch 存在遗传相互作用的保守基因。
