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过程，在哺乳动物生理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，它储存在细胞内的小泡中，类似于哺乳动物脂肪组织中的甘油三酯。子实体内的细胞有两种主要命运。细胞程序性死亡(PCD)是80%的细胞的命运，涉及MazF毒素介导的RNA降解。剩下的细胞在MRPC抗毒素的帮助下产生孢子，MRPC抗毒素是一种主要的发育转录因子。裂解或产孢子的决定是由三个细胞信号调节的，这三个信号也调节甘油三酯的合成。在孢子成熟过程中，前孢子中的脂体消耗碳和能量。经历PCD的细胞中的脂体被释放到子实体中，在那里它们调节发育。该提案解决了两个问题。首先，什么是脂肪的形态成因？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信号和脂类趋化物质。这些信号将使用涉及不能产生信号的突变体的生物检测来纯化，通过气相色谱/质谱仪进行鉴定，然后合成以证明合成的结构具有活性。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。当毒素和抗毒素达到平衡时，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，而另一些信号则通过产生更多的抗毒素来刺激孢子形成。这项应用是创新的，因为它将组装多达四个关键的拼图，以解决黄花草的子实体形态发生和细胞命运决定的谜题。我们期望发现，发育在很大程度上源于脂肪体脂的合成和利用。这种脂类是哺乳动物发育和动态平衡的基本特征。这一系统可能会揭示在哺乳动物中尚未发现的新的调控策略。 公共卫生相关性： 公共卫生相关性黄色粘球菌是研究脂体的模型系统，脂体是细胞内的囊泡，类似于哺乳动物脂肪组织中发现的，其甘油三酯是导致人类肥胖的原因。黄曲霉脂质体脂还含有血浆原，在大脑、肾脏和睾丸中发现的磷脂，其在人类中的功能尚不清楚。这项工作可能揭示粘球菌的新结构和调节策略，这些策略在调节哺乳动物组织中的脂肪代谢方面具有尚未发现的对应物。

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. PUBLIC HEALTH RELEVANCE: Public Health Relevance Myxococcus xanthus is a model system for the study of lipid bodies, intracellular vesicles resembling those found in mammalian adipose tissue whose triglycerides are responsible for human obesity. M. xanthus lipid body lipids also contain plasmalogens, phospholipids found in brain, kidney, and testes whose function in humans remains unknown. This work may reveal novel structural and regulatory strategies in Myxococcus that have as yet undiscovered counterpoints in regulating lipid metabolism in mammalian tissues.