Disruption of homeostatic microRNA (miRNA) expression levels is known to cause human neuropathology. However, the gene regulatory and phenotypic effects of altering a miRNA’s in vivo abundance (rather than its binary gain or loss) are not well understood. By genetic combination, we generated an allelic series of mice expressing varying levels of miR-218, a motor neuron-selective gene regulator associated with motor neuron disease. Titration of miR-218 cellular dose unexpectedly revealed complex, non-ratiometric target mRNA dose responses and distinct gene network outputs. A non-linearly responsive regulon exhibited a steep miR-218 dose-dependent threshold in repression that, when crossed, resulted in severe motor neuron synaptic failure and death. This work demonstrates that a miRNA can govern distinct gene network outputs at different expression levels and that miRNA-dependent phenotypes emerge at particular dose ranges because of hidden regulatory inflection points of their underlying gene networks.

已知稳态 microRNA (miRNA) 表达水平的破坏会导致人类神经病理学。然而，体内改变 miRNA 的基因调控和表型效应丰度（而不是它的二元收益或损失）还没有被很好地理解。通过遗传组合，我们生成了一系列表达不同水平 miR-218 的等位基因小鼠，miR-218 是一种与运动神经元疾病相关的运动神经元选择性基因调节因子。miR-218 细胞剂量的滴定出人意料地揭示了复杂的、非比例的靶 mRNA 剂量反应和不同的基因网络输出。非线性反应调节子在抑制中表现出陡峭的 miR-218 剂量依赖性阈值，当越过该阈值时，会导致严重的运动神经元突触衰竭和死亡。这项工作表明 miRNA 可以在不同的表达水平上控制不同的基因网络输出，并且由于其潜在基因网络的隐藏调节拐点，miRNA 依赖性表型在特定剂量范围内出现。