Department of Physiology, Department of Biomedicine & Health Sciences, Catholic Neuroscience Institute, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea.
Department of Pharmacology, Department of Biomedicine & Health Sciences, Catholic Neuroscience Institute, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea.
Mol Neurobiol. 2019 May;56(5):3780-3795. doi: 10.1007/s12035-018-1297-0. Epub 2018 Sep 10.
Many neurodevelopmental disorders feature learning and memory difficulties. Regulation of neurite outgrowth during development is critical for neural plasticity and memory function. Here, we show a novel regulator of neurite outgrowth during cortical neurogenesis, Lin28, which is an RNA-binding protein. Persistent Lin28 upregulation by in utero electroporation at E14.5 resulted in neurite underdevelopment during cortical neurogenesis. We also showed that Lin28-overexpressing cells had an attenuated response to excitatory inputs and altered membrane properties including higher input resistance, slower action potential repolarization, and smaller hyperpolarization-activated cation currents, supporting impaired neuronal functionality in Lin28-electroporated mice. When we ameliorated perturbed Lin28 expression by siRNA, Lin28-induced neurite underdevelopment was rescued with reduction of Lin28-downstream molecules, high mobility group AT-Hook 2, and insulin-like growth factor 1 receptor. Finally, Lin28-electroporated mice showed significant memory deficits as assessed by the Morris water maze test. Taken together, these findings demonstrate a new role and the essential requirement of Lin28 in developmental control of neurite outgrowth, which has an impact on synaptic plasticity and spatial memory. These findings suggest that targeting Lin28 may attenuate intellectual disabilities by correction of impaired dendritic complexity, providing a novel therapeutic candidate for treating neurodevelopmental disorders.
许多神经发育障碍都表现出学习和记忆困难。发育过程中神经突生长的调节对于神经可塑性和记忆功能至关重要。在这里，我们展示了一种新的皮质神经发生中神经突生长的调节因子 Lin28，它是一种 RNA 结合蛋白。在 E14.5 时通过宫内电穿孔持续上调 Lin28 会导致皮质神经发生过程中神经突发育不良。我们还表明，Lin28 过表达细胞对兴奋性输入的反应减弱，并且改变了膜特性，包括更高的输入电阻、更慢的动作电位复极化和更小的超极化激活阳离子电流，支持 Lin28 电穿孔小鼠中神经元功能受损。当我们通过 siRNA 改善失调的 Lin28 表达时，Lin28 诱导的神经突发育不良通过减少 Lin28 下游分子高迁移率族 AT 盒结合蛋白 2 和胰岛素样生长因子 1 受体得到挽救。最后，Lin28 电穿孔小鼠在 Morris 水迷宫测试中表现出明显的记忆缺陷。总之，这些发现表明 Lin28 在神经突生长的发育调控中具有新的作用和必要性，这对突触可塑性和空间记忆有影响。这些发现表明，通过纠正受损的树突复杂性来靶向 Lin28 可能会减轻智力障碍，为治疗神经发育障碍提供一种新的治疗候选药物。
