An In Silico Agent-Based Model Demonstrates Reelin Function in Directing Lamination of Neurons during Cortical Development
An In Silico Agent-Based Model Demonstrates Reelin Function in Directing Lamination of Neurons during Cortical Development
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DOI：
10.1371/journal.pone.0110415
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发表时间：
2014-10-21
期刊：
影响因子：
3.7
通讯作者：
Landman, Kerry A.
中科院分区：
文献类型：
--
作者：
Caffrey, James R.;Hughes, Barry D.;Landman, Kerry A.
新皮层的六层特征源于锥体神经元在发育过程中的正确定位，这一过程的改变可能导致智力残疾和发育迟缓。当神经元不能正确地从生发区迁移或不能在皮层板内的正确层状位置停止迁移时，就会出现皮质发育畸形。Reelin信号通路对正确的神经元定位至关重要，因为Reelin的缺失会导致部分倒置的皮层。Reelin的确切生物学功能仍然存在争议，围绕其作为化学引诱剂或迁移神经元的停止信号的作用存在争议。为了进一步研究这一点，我们开发了一个基于硅代理的皮层形成模型。使用该模型，我们测试了神经元运动的四种生物学上合理的假设，以及神经元运动丧失的四种生物学上合理的假设（从迁移转换）。对已知的小鼠皮质层结构（野生型、Reelin-null突变体、Dab1-null突变体和条件型Dab1突变体）应用16种运动和转换规则组合矩阵。使用这种方法，许多运动和转换机制的组合可以被拒绝。例如，该模型不支持Reelin作为排斥或停止信号。相反，这项研究非常有力地支持了糖蛋白Reelin作为神经元化学引诱剂的观点。此外，对于转换机制最可行的主张是，转换受到附近已经转换的神经元的运动神经元感知的影响。因此，该模型有助于阐明Reelin在神经元迁移和皮层发育过程中的功能。
The characteristic six-layered appearance of the neocortex arises from the correct positioning of pyramidal neurons during development and alterations in this process can cause intellectual disabilities and developmental delay. Malformations in cortical development arise when neurons either fail to migrate properly from the germinal zones or fail to cease migration in the correct laminar position within the cortical plate. The Reelin signalling pathway is vital for correct neuronal positioning as loss of Reelin leads to a partially inverted cortex. The precise biological function of Reelin remains controversial and debate surrounds its role as a chemoattractant or stop signal for migrating neurons. To investigate this further we developed an in silico agent-based model of cortical layer formation. Using this model we tested four biologically plausible hypotheses for neuron motility and four biologically plausible hypotheses for the loss of neuron motility (conversion from migration). A matrix of 16 combinations of motility and conversion rules was applied against the known structure of mouse cortical layers in the wild-type cortex, the Reelin-null mutant, the Dab1-null mutant and a conditional Dab1 mutant. Using this approach, many combinations of motility and conversion mechanisms can be rejected. For example, the model does not support Reelin acting as a repelling or as a stopping signal. In contrast, the study lends very strong support to the notion that the glycoprotein Reelin acts as a chemoattractant for neurons. Furthermore, the most viable proposition for the conversion mechanism is one in which conversion is affected by a motile neuron sensing in the near vicinity neurons that have already converted. Therefore, this model helps elucidate the function of Reelin during neuronal migration and cortical development.