Torres-Berrío Angélica, Lopez Juan Pablo, Bagot Rosemary C, Nouel Dominique, Dal Bo Gregory, Cuesta Santiago, Zhu Lei, Manitt Colleen, Eng Conrad, Cooper Helen M, Storch Kai-Florian, Turecki Gustavo, Nestler Eric J, Flores Cecilia
Integrated Program in Neuroscience, Montréal, Québec, Canada; Douglas Mental Health University Institute; Montréal, Québec, Canada.
Department of Human Genetics; Montréal, Québec, Canada; McGill Group for Suicide Studies, Montréal, Québec, Canada.
Biol Psychiatry. 2017 Feb 15;81(4):306-315. doi: 10.1016/j.biopsych.2016.08.017. Epub 2016 Aug 18.
Variations in the expression of the Netrin-1 guidance cue receptor DCC (deleted in colorectal cancer) appear to confer resilience or susceptibility to psychopathologies involving prefrontal cortex (PFC) dysfunction.
With the use of postmortem brain tissue, mouse models of defeat stress, and in vitro analysis, we assessed microRNA (miRNA) regulation of DCC and whether changes in DCC levels in the PFC lead to vulnerability to depression-like behaviors.
We identified miR-218 as a posttranscriptional repressor of DCC and detected coexpression of DCC and miR-218 in pyramidal neurons of human and mouse PFC. We found that exaggerated expression of DCC and reduced levels of miR-218 in the PFC are consistent traits of mice susceptible to chronic stress and of major depressive disorder in humans. Remarkably, upregulation of Dcc in mouse PFC pyramidal neurons causes vulnerability to stress-induced social avoidance and anhedonia.
These data are the first demonstration of microRNA regulation of DCC and suggest that, by regulating DCC, miR-218 may be a switch of susceptibility versus resilience to stress-related disorders.
神经纤毛蛋白-1导向因子受体DCC（结直肠癌缺失基因）表达的变化似乎赋予了对涉及前额叶皮质（PFC）功能障碍的精神病理学的恢复力或易感性。
我们使用死后脑组织、应激失败小鼠模型和体外分析，评估了微小RNA（miRNA）对DCC的调控以及PFC中DCC水平的变化是否导致对抑郁样行为的易感性。
我们鉴定出miR-218是DCC的转录后抑制因子，并在人和小鼠PFC的锥体神经元中检测到DCC和miR-218的共表达。我们发现，PFC中DCC的过度表达和miR-218水平的降低是易患慢性应激的小鼠和人类重度抑郁症的一致特征。值得注意的是，小鼠PFC锥体神经元中Dcc的上调会导致对应激诱导的社交回避和快感缺失的易感性。
这些数据首次证明了miRNA对DCC的调控，并表明通过调节DCC，miR-218可能是应激相关疾病易感性与恢复力的一个开关。
