EGFR signaling promotes self-renewal through the establishment of cell polarity in Drosophila follicle stem cells.
EGFR signaling promotes self-renewal through the establishment of cell polarity in Drosophila follicle stem cells.
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DOI：
10.7554/elife.04437
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发表时间：
2014-12-01
期刊：
影响因子：
7.7
通讯作者：
Nystul TG
中科院分区：
文献类型：
--
作者：
Castanieto A;Johnston MJ;Nystul TG
上皮干细胞不对称分裂，这样一个子细胞补充干细胞库，而另一个分化。我们发现，在果蝇卵巢上皮卵泡干细胞（FSC）谱系中，表皮生长因子受体（EGFR）信号在FSC中特异性地发挥作用，促进FSC独特的部分极化状态，在整个谱系中建立顶基极性，并促进FSC在生态位中的维持。此外，我们还发现了EGFR信号与细胞极性调节因子肝激酶B1 （LKB1）之间的新联系，这表明EGFR信号通过Ras-Raf-MEK-Erk途径和LKB1 - ampk途径抑制根尖身份。顶基极性的发育是FSCs与其子细胞之间最早可见的差异，我们的研究结果表明，egfr介导的顶基极性调控对于干细胞和子细胞命运的分离至关重要。DOI: http://dx.doi.org/10.7554/eLife.04437.001干细胞是一种特殊的细胞，它可以分裂产生另一个干细胞，再加上一个细胞，继续在体内发挥特定的作用。第二个细胞变成特定类型细胞的过程称为分化。人体包含许多不同类型的干细胞，如神经干细胞，它会继续形成神经系统，上皮干细胞，它会在体内产生各种类型的表面，如皮肤和肠壁。许多类型的上皮细胞是极化的，这意味着它们有三个不同的面或结构域：一个面向下层组织的基底结构域；在对侧的一顶域；在顶域和基域之间有一个侧域。细胞极性如何在上皮细胞中建立的细节尚不完全清楚，但它被认为起源于上皮干细胞的分裂。现在，通过研究果蝇卵巢中的卵泡干细胞，Castanieto等人已经表明，EGFR信号传导（表皮生长因子受体信号的简称）在确定干细胞和分化细胞之间的差异中起着核心作用。EGFR信号在一定程度上通过促进干细胞的“部分极化状态”来实现这一点：这种状态的特征是存在基域和侧域，但没有顶域。在完全极化的细胞中，顶端结构域和外侧结构域共同工作，以确保所有三个结构域在细胞表面保持分离，因此令人惊讶地发现，干细胞可以在没有顶端结构域的情况下保持基底结构域和外侧结构域。Castanieto等人提出，这一壮举是通过EGFR信号传导实现的，它激活了多种蛋白质，包括已知调节细胞极性的LKB1。这项工作强烈表明，细胞极性的变化是上皮干细胞和分化细胞之间最早出现的差异之一。在未来，确定这些细胞极性的差异是否会导致干细胞和分化细胞在组织中扮演不同的角色将是很重要的。例如，可能是干细胞缺乏顶端结构域，从而使它们免受组织中促进分化的信号的影响，从而使它们保持未分化状态。相反，分化细胞中顶端结构域的发育可能使其暴露于促进其分化的信号，并使其形成屏障并发挥上皮组织的其他作用。DOI: http://dx.doi.org/10.7554/eLife.04437.002
Epithelial stem cells divide asymmetrically, such that one daughter replenishes the stem cell pool and the other differentiates. We found that, in the epithelial follicle stem cell (FSC) lineage of the Drosophila ovary, epidermal growth factor receptor (EGFR) signaling functions specifically in the FSCs to promote the unique partially polarized state of the FSC, establish apical–basal polarity throughout the lineage, and promote FSC maintenance in the niche. In addition, we identified a novel connection between EGFR signaling and the cell-polarity regulator liver kinase B1 (LKB1), which indicates that EGFR signals through both the Ras–Raf–MEK–Erk pathway and through the LKB1–AMPK pathway to suppress apical identity. The development of apical–basal polarity is the earliest visible difference between FSCs and their daughters, and our findings demonstrate that the EGFR-mediated regulation of apical–basal polarity is essential for the segregation of stem cell and daughter cell fates. DOI: http://dx.doi.org/10.7554/eLife.04437.001 A stem cell is a special cell that divides to produce another stem cell, plus a cell that goes on to perform a specific role in the body. The process by which this second cell becomes a specific type of cell is called differentiation. The body contains many different types of stem cells, such as neural stem cells, which go on to form the nervous system, and epithelial stem cells, which give rise to various types of surfaces in the body, such as the skin and the lining of the intestine. Many types of epithelial cells are polarized, which means they have three distinct sides or domains: a basal domain that faces the underlying tissue; an apical domain on the opposite side; and a lateral domain on the side in between the apical and basal domains. The details of how cell polarity is established in epithelial cells are not fully understood, but it is thought to have its origins in the division of epithelial stem cells. Now, by studying follicle stem cells in the ovaries of fruit flies, Castanieto et al. have shown that a process called EGFR signaling (which is short for epidermal growth factor receptor signaling) has a central role in establishing the difference between the stem cell and the cell that differentiates. EGFR signaling does this, in part, by promoting a ‘partially polarized state’ in the stem cells: this state is characterized by the presence of a basal domain and a lateral domain but no apical domain. In fully polarized cells, the apical and lateral domains work together to ensure that all three domains remain separated on the surface of the cell, so it was surprising to find that the stem cell could maintain basal and lateral domains without an apical domain. Castanieto et al. propose that this feat is achieved by EGFR signaling, which activates a multiple number of proteins, including one called LKB1 that is known to regulate cell polarity. This work strongly suggests that that changes in cell polarity are among the earliest differences to arise between epithelial stem cells and differentiating cells. In the future, it will be important to determine whether these differences in cell polarity cause the stem cells and the differentiating cells to take on different roles in the tissue. For example, it may be that the lack of an apical domain in the stem cells shields them from signals in the tissue that promote differentiation, thus allowing them to remain undifferentiated. Conversely, the development of an apical domain in the differentiating cells may expose them to signals that promote their differentiation, and also allow them to form a barrier and perform the other roles of epithelial tissue. DOI: http://dx.doi.org/10.7554/eLife.04437.002