Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School and Department of Psychology, Rutgers University, Piscataway, New Jersey 08854, University of California, Berkeley, California 94704, Behavioral Instruments, Hillsborough, New Jersey 08854, and Department of Physiology, Keio University, Tokyo 160-8582, Japan.
J Neurosci. 2014 Mar 5;34(10):3674-86. doi: 10.1523/JNEUROSCI.3703-13.2014.
The proper functions of cortical circuits are dependent upon both appropriate neuronal subtype specification and their maturation to receive appropriate signaling. These events establish a balanced circuit that is important for learning, memory, emotion, and complex motor behaviors. Recent research points to mRNA metabolism as a key regulator of this development and maturation process. Hu antigen D (HuD), an RNA-binding protein, has been implicated in the establishment of neuronal identity and neurite outgrowth in vitro. Therefore, we investigated the role of HuD loss of function on neuron specification and dendritogenesis in vivo using a mouse model. We found that loss of HuD early in development results in a defective early dendritic overgrowth phase and pervasive deficits in neuron specification in the lower neocortical layers and defects in dendritogenesis in the CA3 region of the hippocampus. Subsequent behavioral analysis revealed a deficit in performance of a hippocampus-dependent task: the Morris water maze. Further, HuD knock-out (KO) mice exhibited lower levels of anxiety than their wild-type counterparts and were overall less active. Last, we found that HuD KO mice are more susceptible to auditory-induced seizures, often resulting in death. Our findings suggest that HuD is necessary for the establishment of neocortical and hippocampal circuitry and is critical for their function.
皮质回路的正常功能既依赖于适当的神经元亚型特异性，也依赖于其成熟以接收适当的信号。这些事件建立了一个平衡的回路，对于学习、记忆、情感和复杂的运动行为都很重要。最近的研究指出，mRNA 代谢是这个发育和成熟过程的关键调节剂。Hu 抗原 D（HuD）是一种 RNA 结合蛋白，已被牵涉到体外神经元身份和突起生长的建立中。因此，我们使用小鼠模型研究了 HuD 功能丧失对体内神经元特化和树突发生的作用。我们发现，早期发育过程中 HuD 的缺失导致早期树突过度生长阶段出现缺陷，以及下皮质层神经元特化的普遍缺陷，以及海马 CA3 区树突发生的缺陷。随后的行为分析显示，在一项依赖海马体的任务：Morris 水迷宫中表现出缺陷。此外，HuD 敲除（KO）小鼠比其野生型对照表现出更低的焦虑水平，且整体活动水平更低。最后，我们发现 HuD KO 小鼠更容易受到听觉诱导的癫痫发作的影响，经常导致死亡。我们的研究结果表明，HuD 对于建立新皮质和海马体回路是必要的，并且对于它们的功能至关重要。
