Department of Electrical and Computer Engineering, Purdue University, West Lafayette, IN, USA.
J R Soc Interface. 2012 May 7;9(70):1073-83. doi: 10.1098/rsif.2011.0547. Epub 2011 Oct 19.
Morphogens are secreted molecules that specify cell-fate organization in developing tissues. Patterns of gene expression or signalling immediately downstream of many morphogens such as the bone morphogenetic protein (BMP) decapentaplegic (Dpp) are highly reproducible and robust to perturbations. This contrasts starkly with our expectation of a noisy interpretation that would arise out of the experimentally determined low concentration (approximately picomolar) range of Dpp activity, tight receptor binding and very slow kinetic rates. To investigate mechanisms by which the intrinsic noise can be attenuated in Dpp signalling, we focus on a class of secreted proteins that bind to Dpp in the extracellular environment and play an active role in regulating Dpp/receptor interactions. We developed a stochastic model of Dpp signalling in Drosophila melanogaster and used the model to quantify the extent that stochastic fluctuations would lead to errors in spatial patterning and extended the model to investigate how a surface-associated BMP-binding protein (SBP) such as Crossveinless-2 (Cv-2) may buffer out signalling noise. In the presence of SBPs, fluctuations in the level of ligand-bound receptor can be reduced by more than twofold depending on parameter values for the intermediate transition states. Regulation of receptor-ligand interactions by SBPs may also increase the frequency of stochastic fluctuations providing a separation of timescales between high-frequency receptor equilibration and slower morphogen patterning. High-frequency noise generated by SBP regulation is easily attenuated by the intracellular network creating a system that imitates the performance of a simple low-pass filter common in audio and communication applications. Together, these data indicate that one of the benefits of receptor-ligand regulation by secreted non-receptors may be greater reliability of morphogen patterning mechanisms.
形态发生素是分泌的分子，可在发育组织中指定细胞命运组织。许多形态发生素（例如骨形态发生蛋白（BMP）decapentaplegic（Dpp））下游的基因表达或信号模式非常具有再现性，并且对干扰具有很强的鲁棒性。这与我们的预期形成鲜明对比，即由于 Dpp 活性的实验确定的低浓度（约皮摩尔）范围，紧密的受体结合和非常缓慢的动力学速率，会产生嘈杂的解释。为了研究内在噪声如何在 Dpp 信号转导中减弱的机制，我们专注于一类分泌蛋白，这些蛋白在细胞外环境中与 Dpp 结合，并在调节 Dpp/受体相互作用中发挥积极作用。我们开发了一种果蝇 Dpp 信号转导的随机模型，并使用该模型量化了随机波动导致空间图案错误的程度，并扩展了该模型以研究诸如 Crossveinless-2（Cv-2）之类的表面相关 BMP 结合蛋白（SBP）如何缓冲信号噪声。在存在 SBPs 的情况下，取决于中间过渡态的参数值，配体结合受体的水平波动可以减少两倍以上。SBPs 对受体-配体相互作用的调节还可以增加随机波动的频率，从而在高频受体平衡和较慢的形态发生模式之间提供时间尺度的分离。由 SBP 调节产生的高频噪声很容易被细胞内网络衰减，从而创建了一个系统，该系统模仿了在音频和通信应用中常见的简单低通滤波器的性能。这些数据表明，分泌非受体对受体-配体相互作用的调节的好处之一可能是形态发生模式形成机制的可靠性更高。
