Esser Axel T, Smith Kyle C, Weaver James C, Levin Michael
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Dev Dyn. 2006 Aug;235(8):2144-59. doi: 10.1002/dvdy.20870.
Gap junctional communication is important for embryonic morphogenesis. However, the factors regulating the spatial properties of small molecule signal flows through gap junctions remain poorly understood. Recent data on gap junctions, ion transporters, and serotonin during left-right patterning suggest a specific model: the net unidirectional transfer of small molecules through long-range gap junctional paths driven by an electrophoretic mechanism. However, this concept has only been discussed qualitatively, and it is not known whether such a mechanism can actually establish a gradient within physiological constraints. We review the existing functional data and develop a mathematical model of the flow of serotonin through the early Xenopus embryo under an electrophoretic force generated by ion pumps. Through computer simulation of this process using realistic parameters, we explored quantitatively the dynamics of morphogen movement through gap junctions, confirming the plausibility of the proposed electrophoretic mechanism, which generates a considerable gradient in the available time frame. The model made several testable predictions and revealed properties of robustness, cellular gradients of serotonin, and the dependence of the gradient on several developmental constants. This work quantitatively supports the plausibility of electrophoretic control of morphogen movement through gap junctions during early left-right patterning. This conceptual framework for modeling gap junctional signaling -- an epigenetic patterning mechanism of wide relevance in biological regulation -- suggests numerous experimental approaches in other patterning systems.
缝隙连接通讯对于胚胎形态发生至关重要。然而，调节小分子信号通过缝隙连接的空间特性的因素仍知之甚少。最近关于左右模式形成过程中缝隙连接、离子转运体和血清素的数据提出了一个特定模型：小分子通过由电泳机制驱动的长距离缝隙连接路径进行净单向转移。然而，这一概念仅得到了定性讨论，尚不清楚这种机制在生理限制条件下是否真的能建立一个梯度。我们回顾了现有的功能数据，并建立了一个数学模型，用于描述在离子泵产生的电泳力作用下血清素通过非洲爪蟾早期胚胎的流动情况。通过使用实际参数对这一过程进行计算机模拟，我们定量地探究了形态发生素通过缝隙连接移动的动力学，证实了所提出的电泳机制的合理性，该机制在可用的时间框架内产生了相当大的梯度。该模型做出了几个可测试的预测，并揭示了其稳健性、血清素的细胞梯度以及梯度对几个发育常数的依赖性等特性。这项工作定量地支持了在早期左右模式形成过程中通过缝隙连接对形态发生素移动进行电泳控制的合理性。这个用于模拟缝隙连接信号传导的概念框架——一种在生物调节中具有广泛相关性的表观遗传模式形成机制——为其他模式形成系统提出了众多实验方法。
