Microsoft Research, 21 Station Road, Cambridge, CB1 2FB, UK.
Randall Centre for Cell and Molecular Biophysics, King's College London, London, WC2R 2LS, UK.
Nat Commun. 2020 Nov 2;11(1):5545. doi: 10.1038/s41467-020-19098-w.
During development, cells gain positional information through the interpretation of dynamic morphogen gradients. A proposed mechanism for interpreting opposing morphogen gradients is mutual inhibition of downstream transcription factors, but isolating the role of this specific motif within a natural network remains a challenge. Here, we engineer a synthetic morphogen-induced mutual inhibition circuit in E. coli populations and show that mutual inhibition alone is sufficient to produce stable domains of gene expression in response to dynamic morphogen gradients, provided the spatial average of the morphogens falls within the region of bistability at the single cell level. When we add sender devices, the resulting patterning circuit produces theoretically predicted self-organised gene expression domains in response to a single gradient. We develop computational models of our synthetic circuits parameterised to timecourse fluorescence data, providing both a theoretical and experimental framework for engineering morphogen-induced spatial patterning in cell populations.
在发育过程中，细胞通过解释动态形态发生梯度来获得位置信息。一种解释相反形态发生梯度的拟议机制是下游转录因子的相互抑制，但在自然网络中分离这种特定模体的作用仍然是一个挑战。在这里，我们在大肠杆菌种群中设计了一种合成的形态发生诱导的相互抑制回路，并表明相互抑制本身足以产生对动态形态发生梯度的稳定基因表达域，前提是形态发生剂的空间平均值落在单细胞水平的双稳区。当我们添加发送器设备时，所产生的图案形成电路会根据单个梯度产生理论上预测的自组织基因表达域。我们对合成电路进行了参数化的计算模型，以适应时间荧光数据，为在细胞群体中进行形态发生诱导的空间图案形成提供了理论和实验框架。
