Guisoni Nara, Martinez-Corral Rosa, Garcia-Ojalvo Jordi, de Navascués Joaquín
Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), Dr Aiguader 88, Barcelona 08003, Spain.
Instituto de Física de Líquidos y Sistemas Biológicos (IFLYSIB), CONICET CCT-La Plata and Universidad Nacional de La Plata, Calle 59-789, La Plata 1900, Argentina.
Development. 2017 Apr 1;144(7):1177-1186. doi: 10.1242/dev.137950. Epub 2017 Feb 7.
Cell fate determination by lateral inhibition via Notch/Delta signalling has been extensively studied. Most formalised models consider Notch/Delta interactions in fields of cells, with parameters that typically lead to symmetry breaking of signalling states between neighbouring cells, commonly resulting in salt-and-pepper fate patterns. Here, we consider the case of signalling between isolated cell pairs, and find that the bifurcation properties of a standard mathematical model of lateral inhibition can lead to stable symmetric signalling states. We apply this model to the adult intestinal stem cell (ISC) of , the fate of which is stochastic but dependent on the Notch/Delta pathway. We observe a correlation between signalling state in cell pairs and their contact area. We interpret this behaviour in terms of the properties of our model in the presence of population variability in contact areas, which affects the effective signalling threshold of individual cells. Our results suggest that the dynamics of Notch/Delta signalling can contribute to explain stochasticity in stem cell fate decisions, and that the standard model for lateral inhibition can account for a wider range of developmental outcomes than previously considered.
通过Notch/Delta信号通路的侧向抑制来决定细胞命运已经得到了广泛研究。大多数形式化模型考虑细胞群体中Notch/Delta的相互作用，其参数通常会导致相邻细胞间信号状态的对称性破缺，通常会产生黑白相间的命运模式。在这里，我们考虑孤立细胞对之间的信号传导情况，发现侧向抑制的标准数学模型的分岔特性可导致稳定的对称信号状态。我们将此模型应用于成年小鼠的肠道干细胞（ISC），其命运是随机的，但依赖于Notch/Delta通路。我们观察到细胞对中的信号状态与其接触面积之间存在相关性。我们根据模型在接触面积存在群体变异性时的特性来解释这种行为，这种变异性会影响单个细胞的有效信号阈值。我们的结果表明，Notch/Delta信号传导的动力学有助于解释干细胞命运决定中的随机性，并且侧向抑制的标准模型可以解释比以前认为的更广泛的发育结果。
