Signal Amplification Mechanisms in Primary Cell Determination

动物从卵子到成体的生长需要产生成千上万种不同的细胞。每个细胞必须对决定其最终命运的分子信号做出正确的反应，因为错误的后果是死亡或疾病。细胞如何区分彼此之间仅有细微差别的信号，这一问题尤其具有挑战性。一个教科书上的例子是果蝇的性别决定，然而，正如这部作品所显示的那样，教科书版本在基本细节上是错误的。这个项目利用独特的遗传工具来确定苍蝇是如何判断它们是有一个X染色体，还是作为雄性发育成两个X染色体，并作为雌性发育。人们的期望是，对信号的反应是以很小的步骤发生的，而且这些步骤相互加强。其结果是将微小的初始差异放大为可靠的反应。雌性首先开始发育，因为Two-X信号略高。这导致了一系列事件，同时增加了女性的计划，同时抑制了男性的计划，从而确保了女性的适当发展。反过来，男性较低的初始信号会使执行女性计划变得越来越困难，从而促进男性发育。由于所涉及的分子是动物发育的一般调节因素，它们在苍蝇性交中发挥作用的机制应该适用于动物发育的许多方面。这项工作的更广泛影响取决于类比原则。像苍蝇这样的实验系统可以揭示接近活着有机体实际存在的细节水平。这让在不太容易处理的系统中的研究人员找到了通往正确答案的捷径。性别决定在教科书中的地位加强了课程和类比的教育和科学影响，但也使纠正教科书变得势在必行。

Growth of an animal from an egg to an adult requires the generation of thousands of different kinds of cells. Each cell must respond correctly to the molecular signals that specify its ultimate fate, for the consequences of mistakes are death or disease. The question of how cells discriminate between signals that differ only subtly from one another is particularly challenging. A textbook example is sex determination in the fruit fly, Drosophila, yet, as shown in this work, the textbook version is wrong in fundamental details. This project exploits unique genetic tools to determine how flies tell whether they have one X chromosome and develop as males or two Xs and grow as females. The expectation is that responses to signals occur in small steps and that the steps reinforce one another. The result is an amplification of a small initial difference into a reliable response. Females initiate development first because of the slightly higher two-X signal. This leads to a chain of events that simultaneously increases the female program while dampening the male one, thus ensuring proper female development. Reciprocally, the lower initial signal in males promotes male development by making it progressively harder to carry out the female program. Because the molecules involved are general regulators of animal development, the mechanisms by which they work in fly sex should apply to many aspects of animal development. The broader impact of this work rests on the principle of analogy. Experimental systems like the fly can reveal levels of detail that approaches what actually exists in the living organism. This lets researchers in less tractable systems take shortcuts to the correct answers. The textbook status of sex determination reinforces the educational and scientific impacts of the lessons and analogies, but also makes it imperative to correct the textbooks.