Dynamics and regulatory logic of the endodermal cell-fate decision in C. elegans

描述(申请人提供)：这个项目使用定量测量和数学模型来了解线虫秀丽线虫是如何指定内皮细胞命运的。决定细胞命运的遗传网络的核心由一小群转录因子组成，这些转录因子的目标是激活内皮主调控基因的表达。这个网络的突变可能会产生令人惊讶和不确定的影响。最上游基因的突变是部分穿透性的，导致遗传和环境相同的胚胎在是否发育内胚层方面有所不同。虽然已知这种突变揭示了基因在网络中表达的阈值，但这个阈值是如何产生的还不清楚。此外，该网络包含几对似乎部分冗余的并列基因，使网络对某些突变具有很强的抵抗力。这里提出的实验将应用和测试一个数学模型框架，用于发育遗传网络中的转录调控。我们的目标是通过对转基因线虫工程菌株的高分辨率基因表达测量来估计该模型的关键参数。通过这些测量，我们将能够对这些蠕虫的正常内胚层规格进行建模，并预测不同扰动对网络的影响。通过在建模和实验之间迭代，我们将完善我们对开发过程中如何控制细胞类型规范的理解。线虫作为遗传和发育研究的优势物种之一，是发育系统生物学模式生物的自然选择。它的许多易驯化、遗传和发育的优势传递给它的近亲，因此线虫属也迅速成为进化系统生物学的模式支系。

DESCRIPTION (provided by applicant): This project uses quantitative measurements and mathematical modeling to understand how the nematode Caenorhabditis elegans specifies endodermal cell fate. The core of the genetic network governing this cell fate decision consists of a small group of transcription factors whose objective is to activate the expression of an endodermal master regulatory gene. Mutations to this network can have surprising and indeterminate effects. A mutation in the most upstream gene is partially penetrant, resulting in genetically and environmentally identical embryos differing in whether they develop endoderm or not. Although it is known that this mutation reveals a threshold for gene expression in the network, how this threshold is generated is unclear. Moreover, the network contains several pairs of paralogs that appear to be partially redundant, making the network robust against some mutations. The experiments proposed here will apply and test a mathematical modeling framework for transcriptional regulation in developmental genetic networks. The goal is to estimate key parameters of the model from high resolution gene expression measurements on engineered transgenic strains of C. elegans. With these measurements we will be able to model normal endodermal specification in these worms and predict the effects of different perturbations to the network. By iterating between modeling and experimentation, we will refine our understanding of how cell-type specification is controlled during development. As one of the preeminent species for genetic and developmental studies, C. elegans is a natural choice for a model organism for developmental systems biology. Many of its advantages for tractability, genetics, and development carry over to its close relatives, and so the Caenorhabditis genus is fast becoming a model clade for evolutionary systems biology as well.