Broadly heterogeneous activation of the master regulator for sporulation in Bacillus subtilis
Broadly heterogeneous activation of the master regulator for sporulation in Bacillus subtilis
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DOI：
10.1073/pnas.1002499107
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发表时间：
2010-05-04
影响因子：
11.1
通讯作者：
Losick, Richard M.
中科院分区：
文献类型：
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作者：
Chastanet, Arnaud;Vitkup, Dennis;Losick, Richard M.
研究发育调控网络如何决定细胞命运的模型系统是枯草芽孢杆菌中的孢子形成。孢子形成的主要调节因子是Spo0A，其通过磷酸化经由磷酸化继电器激活，磷酸化继电器受到三个正反馈回路的影响。然而，最终形成孢子的决定是随机的，因为即使在最佳条件下，也只有一部分种群形成孢子。先前假设Spo0A的激活并因此进入孢子形成受到由一个或多个反馈环介导的信号转换。在这里，我们重新调查的基础上双峰孢子形成。我们发现，没有一个反馈回路是速率限制Spo0A的合成和磷酸化。相反，这些环确保了中继组件的及时供应，以提高磷酸化Spo0A的水平，通过中继的磷酸盐通量限制了Spo0A的激活和孢子形成。此外，Spo0A控制下的基因没有表现出双峰模式的表达，如预期的开关。相反，我们观察到Spo0A激活的高度异质性模式，其随时间以非线性方式增加。我们提出了一个计算模型的非线性增加，并提出磷酸化是一个噪声发生器，只有达到阈值水平的磷酸化Spo0A孢子化的细胞。
A model system for investigating how developmental regulatory networks determine cell fate is spore formation in Bacillus subtilis. The master regulator for sporulation is Spo0A, which is activated by phosphorylation via a phosphorelay that is subject to three positive feedback loops. The ultimate decision to sporulate is, however, stochastic in that only a portion of the population sporulates even under optimal conditions. It was previously assumed that activation of Spo0A and hence entry into sporulation is subject to a bistable switch mediated by one or more feedback loops. Here we reinvestigate the basis for bimodality in sporulation. We show that none of the feedback loops is rate limiting for the synthesis and phosphorylation of Spo0A. Instead, the loops ensure a just-in-time supply of relay components for rising levels of phosphorylated Spo0A, with phosphate flux through the relay being limiting for Spo0A activation and sporulation. In addition, genes under Spo0A control did not exhibit a bimodal pattern of expression as expected for a bistable switch. In contrast, we observed a highly heterogeneous pattern of Spo0A activation that increased in a nonlinear manner with time. We present a computational model for the nonlinear increase and propose that the phosphorelay is a noise generator and that only cells that attain a threshold level of phosphorylated Spo0A sporulate.