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首页> 外文期刊>PLoS One >Mathematical Modeling of Sub-Cellular Asymmetry of Fat-Dachsous Heterodimer for Generation of Planar Cell Polarity
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Mathematical Modeling of Sub-Cellular Asymmetry of Fat-Dachsous Heterodimer for Generation of Planar Cell Polarity

机译：脂肪-平面异源二聚体亚细胞不对称的数学建模

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Planar Cell Polarity (PCP) is an evolutionarily conserved characteristic of animal tissues marked by coordinated polarization of cells or structures in the plane of a tissue. In insect wing epithelium, for instance, PCP is characterized by en masse orientation of hairs orthogonal to its apical-basal axis and pointing along the proximal-distal axis of the organ. Directional cue for PCP has been proposed to be generated by complex sets of interactions amongst three proteins - Fat (Ft), Dachsous (Ds) and Four-jointed (Fj). Ft and Ds are two atypical cadherins, which are phosphorylated by Fj, a Golgi kinase. Ft and Ds from adjacent cells bind heterophilically via their tandem cadherin repeats, and their binding affinities are regulated by Fj. Further, in the wing epithelium, sub-cellular levels of Ft-Ds heterodimers are seen to be elevated at the distal edges of individual cells, prefiguring their PCP. Mechanisms generating this sub-cellular asymmetry of Ft-Ds heterodimer in proximal and distal edges of cells, however, have not been resolved yet. Using a mathematical modeling approach, here we provide a framework for generation of this sub-cellular asymmetry of Ft-Ds heterodimer. First, we explain how the known interactions within Ft-Ds-Fj system translate into sub-cellular asymmetry of Ft-Ds heterodimer. Second, we show that this asymmetric localization of Ft-Ds heterodimer is lost when tissue-level gradient of Fj is flattened, or when phosphorylation of Ft by Fj is abolished, but not when tissue-level gradient of Ds is flattened or when phosphorylation of Ds is abrogated. Finally, we show that distal enrichment of Ds also amplifies Ft-Ds asymmetry. These observations reveal that gradient of Fj expression, phosphorylation of Ft by Fj and sub-cellular distal accumulation of Ds are three critical elements required for generating sub-cellular asymmetry of Ft-Ds heterodimer. Our model integrates the known experimental data and presents testable predictions for future studies.
机译：平面细胞极性（PCP）是动物组织在进化上保守的特征，其特征在于组织平面中细胞或结构的协调极化。例如，在昆虫的翅膀上皮中，五氯苯酚的特征在于与头发的顶基轴正交且沿器官的近－远轴指向的头发的整体定向。已提出PCP的方向提示是通过三种蛋白质-脂肪（Ft），Dachsous（Ds）和四连接（Fj）之间复杂的相互作用集生成的。 Ft和Ds是两个非典型的钙黏着蛋白，被高尔基激酶Fj磷酸化。来自相邻细胞的Ft和Ds通过其串联钙黏着蛋白重复序列​​进行异源结合，其结合亲和力受Fj调控。此外，在翼上皮细胞中，发现Ft-Ds异二聚体的亚细胞水​​平在单个细胞的远端边缘升高，预示了它们的PCP。然而，尚未解决在细胞的近端和远端边缘中这种Ft-Ds异二聚体亚细胞不对称的机制。使用数学建模方法，这里我们提供了一个框架，用于生成Ft-Ds异二聚体的这种亚细胞不对称性。首先，我们解释Ft-Ds-Fj系统内的已知相互作用如何转化为Ft-Ds异二聚体的亚细胞不对称性。其次，我们表明，当Fj的组织水平梯度被展平或Fj的Ft磷酸化被取消时，Ft-Ds异二聚体的这种不对称定位消失了，但是当Ds的组织水平梯度被展平或当Fs的磷酸化被平坦化时，这种不对称定位就消失了。 Ds被废止。最后，我们表明Ds的远端富集也放大了Ft-Ds的不对称性。这些观察结果表明，Fj表达的梯度，Fj的Ft磷酸化和Ds的亚细胞远端积累是产生Ft-Ds异二聚体亚细胞不对称所必需的三个关键要素。我们的模型整合了已知的实验数据，并提出了可检验的预测，以供将来研究。

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