EGFR signaling coordinates patterning with cell survival during Drosophila epidermal development.
EGFR signaling coordinates patterning with cell survival during Drosophila epidermal development.
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DOI：
10.1371/journal.pbio.3000027
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发表时间：
2018-10
期刊：
影响因子：
9.8
通讯作者：
Vincent JP
中科院分区：
文献类型：
--
作者：
Crossman SH;Streichan SJ;Vincent JP
在图案化突变体中经常可以看到广泛的凋亡，这表明组织可以检测并消除潜在的有害错误指定的细胞。在这里，我们表明，果蝇胚胎表皮中的细胞凋亡模式不是对命运错误指定的反应，而是可以用由模式信息决定的位置释放的生存信号分子的有限可用性来解释。在野生型胚胎中，节段级联导致几种表皮生长因子受体配体的节段性生产，包括转化生长因子α(转化生长因子Spitz)和神经调节蛋白，静脉。这导致了信号活性的波动模式，从而阻止了促凋亡基因头部退化缺陷(HID)在整个表皮中的表达。在片段突变体中，当EGFR配体的特定峰无法形成时，信号活性出现缺口，导致一致的HID上调和随后的细胞死亡。这些数据提供了对细胞存活以及适当的组织大小是如何取决于正确的图案的机械理解。缺乏必要模式决定因素的细胞通过凋亡从发育中的组织中消除；这项研究表明，果蝇分段突变体中的细胞死亡是由于EGFR信号模式的破坏，在正常胚胎中，EGFR信号模式与模式信息协调片段大小。在许多组织中，缺陷细胞通过一种称为凋亡的过程来消除。这一过程防止了流氓细胞的出现，这可能对正常生理有害。细胞凋亡在缺乏适当位置信息的胚胎发育中尤为明显，有人认为，在缺乏明确的位置指令的情况下，细胞无法获得明确的命运并因此自杀。在这里，我们使用缺乏必要节段决定因素的突变果蝇胚胎来识别触发细胞凋亡的分子信号，以响应错误的模式。我们发现，细胞不会对相互冲突的命运决定因素做出反应而触发细胞凋亡。相反，错误的图案化会扰乱组织大小控制系统，该系统会移除超大节段中的多余细胞。具体地说，正确的图案化信息会导致存活信号的分段重复产生，从而激活表皮生长因子受体，而这个系统在图案化突变体中会被破坏，从而导致可复制的凋亡模式。我们认为，一个类似的过程，尽管不那么明显，也发生在正常胚胎中。在这样的胚胎中，每个片段最初会包含略多的细胞，然后被削减到由生存信号产生的模式和这些信号的范围指定的大小。我们认为，类似的调控逻辑可以确保在各种发育中的组织中组织图案和大小的协调。
Extensive apoptosis is often seen in patterning mutants, suggesting that tissues can detect and eliminate potentially harmful mis-specified cells. Here, we show that the pattern of apoptosis in the embryonic epidermis of Drosophila is not a response to fate mis-specification but can instead be explained by the limiting availability of prosurvival signaling molecules released from locations determined by patterning information. In wild-type embryos, the segmentation cascade elicits the segmental production of several epidermal growth factor receptor (EGFR) ligands, including the transforming growth factor Spitz (TGFα), and the neuregulin, Vein. This leads to an undulating pattern of signaling activity, which prevents expression of the proapoptotic gene head involution defective (hid) throughout the epidermis. In segmentation mutants, where specific peaks of EGFR ligands fail to form, gaps in signaling activity appear, leading to coincident hid up-regulation and subsequent cell death. These data provide a mechanistic understanding of how cell survival, and thus appropriate tissue size, is made contingent on correct patterning. Cells lacking essential patterning determinants are eliminated from developing tissues by apoptosis; this study shows that cell death in fruit fly segmentation mutants results from disruption of the pattern of EGFR signalling, which in normal embryos coordinates segment size with patterning information. In many tissues, defective cells are eliminated by a process called apoptosis. This process prevents the emergence of rogue cells, which could be detrimental to normal physiology. Apoptosis is particularly apparent in developing embryos that lack appropriate positional information, and it has been suggested that in the absence of clear positional instructions, cells are unable to acquire a defined fate and commit suicide as a result. Here, we have used mutant fruit fly embryos lacking essential segmental determinants to identify the molecular signals that trigger apoptosis in response to mispatterning. We found that cells do not trigger apoptosis in response to conflicting fate determinants. Instead, mispatterning disrupts a tissue size control system that removes excess cells in oversized segments. Specifically, correct patterning information leads to the segmentally repeated production of survival signals, which activate the epidermal growth factor receptor, and this system is disrupted in patterning mutants leading to reproducible patterns of apoptosis. We propose that a similar, though less obvious, process also occurs in normal embryos. In such embryos, each segment would initially comprise a slight excess of cells and would then be trimmed down to a size specified by the pattern of survival signal production and the range of these signals. We suggest that a similar regulatory logic could ensure the coordination of tissue patterning and size in a variety of developing tissues.
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