Myxococcus xanthus signaling and cell fate

描述（由申请人提供）： 黄色粘球菌具有独特的发育程序，在哺乳动物生理学和人类健康方面具有相似之处。早期发育的主要代谢产物是甘油三酯，储存在与哺乳动物脂肪组织相似的细胞内囊泡中。子实体内的细胞有两种主要命运。程序性细胞死亡（PCD）是80%细胞的命运，涉及MazF毒素介导的RNA降解。剩余的细胞在MrpC抗毒素的帮助下形成孢子，MrpC抗毒素是一种主要的发育转录因子。裂解或形成孢子的决定是由三种细胞信号介导的，这些信号也调节甘油三酯的合成。前孢子中的脂质体在孢子成熟过程中被消耗以获取碳和能量。经历PCD的细胞中的脂质体被释放到子实体中，在那里它们调节发育。该提案涉及两个问题。首先，什么是脂质形态发生素？这项工作将通过类似的实验方法确定前三个特定目标中的E-信号，C-信号和脂质化学引诱物。将使用涉及不能产生信号的突变体的生物测定纯化信号，通过气相色谱/质谱法鉴定，然后合成以证明合成结构具有活性。 该提案解决的第二个问题涉及这些信号决定细胞命运的方式。具体目标4将检查感觉通路，特别关注每个信号对毒素/抗毒素相互作用的影响。当毒素和抗毒素平衡时，细胞无法选择命运。我们假设某些信号通过产生更多的游离毒素来诱导PCD，而其他信号通过产生更多的抗毒素来刺激孢子形成。 这个应用程序是创新的，因为它将在M的拼图中组装多达四个基本部分。苍耳子实体形态发生和细胞命运定型。我们期望发现，发展在很大程度上是从脂质体脂质的合成和利用中流出的。这种脂质是哺乳动物发育和体内平衡的基本特征。该系统可能揭示了哺乳动物中尚未发现的新的调控策略。

DESCRIPTION (provided by applicant): Myxococcus xanthus has a unique developmental program with parallels in mammalian physiology and human health. The major metabolic products of early development are triglycerides that are stored in intracellular vesicles similar to those in mammalian adipose tissue. Cells inside the fruiting body have two principle fates. Programmed cell death (PCD), the fate of 80% of the cells, involves MazF toxin-mediated degradation of RNA. The remaining cells sporulate with the help of the MrpC antitoxin, a major developmental transcription factor. The decision to lyse or sporulate is mediated by three cell signals that also regulate synthesis of triglycerides. Lipid bodies in prespores are consumed for carbon and energy during spore maturation. Lipid bodies in cells undergoing PCD are released into the fruiting body where they regulate development. The proposal addresses two questions. First, what are the lipid morphogens? This work will identify the E-signal, the C-signal, and lipid chemoattractants in the first three specific aims through similar experimental approaches. The signals will be purified using bioassays involving mutants that are unable to produce the signals, identified by gas chromatography/mass spectrometry, then synthesized to prove that the synthetic structure has the activity. The second problem addressed by the proposal concerns the manner in which these signals determine cell fate. Specific aim 4 will examine the sensory pathway with a particular focus on the effect of each signal on the toxin/antitoxin interaction. When the toxin and antitoxin are balanced cells fail to choose a fate. We hypothesis that certain signals induce PCD by producing more free toxin while other signals stimulate sporulation by producing more antitoxin. This application is innovative because it will assemble up to four essential pieces in the puzzle of M. xanthus fruiting body morphogenesis and cell fate commitment. We expect to find that development flows in large measure out of the synthesis and utilization of lipid body lipids. Such lipids are an essential feature of mammalian development and homeostasis. This system may reveal novel regulatory strategies that are as yet undiscovered in mammals.