Expanding the mouse repertoire of the synaptic activity-driven transcriptional program with a primate-specific gene: consequences for neuronal functions and cognitive abilities.

Neuronal activity-driven gene expression is the basis for long-lasting adaptations of the brain that are crucial for cognitive functions including learning and memory. The functions of prominent activity-induced genes, such as Bdnf, Egr1 or Npas4, have been mostly examined in rodents. These studies have revealed central, plasticity-related functions for them and it is generally believed that, in principle, their roles are conserved in other mammalian species, including primates and humans. By and large, this is most likely correct. However, the activity-driven gene expression program is not fully generic and not identical between species. For example, it has been shown recently that a small number of the genes that are turned on by synaptic activity in human neurons do not have orthologs in rodents. One of those genes that stands out is the long non-coding RNA gene, LINC00473, a primate-specific gene that is rapidly and particularly robustly upregulated by synaptic activity in human neurons. However, as anticipated for a gene that lacks a mouse counterpart, its functions in neurons are uncharacterized. Since the activity-driven gene expression program is required for cognitive functions, we hypothesize that LINC00473 may have influenced the evolution of brain functions in the lineage leading to humans. Our preliminary data show that humanizing mouse neurons with LINC00473 expression affects plasticity-associated processes, a result that is in line with our hypothesis. In this project, we propose to use gain-of-function experiments in mouse neurons in culture and in mice in vivo, as well as loss-of-function approaches with human iPS cell-derived neurons to study the impact of the primate-specific gene, LINC00473 on neuronal morphology, intracellular signaling, gene regulation and electrophysiological properties, as well as the underlying mechanisms. Behavior studies will be done to examine if humanizing mouse neurons via expansion of the mouse transcriptome with an eminent primate-specific, activity responsive gene affects cognitive performance. Identification of the functions of LINC00473 in neurons may reveal mechanisms that have taken part in driving evolutionary enhancement of human cognitive abilities.

神经活性驱动的基因表达是大脑持久适应的基础，这对于包括学习和记忆在内的认知功能至关重要。突出活性诱导的基因（例如BDNF，EGR1或NPAS4）的功能主要在啮齿动物中进行了检查。这些研究揭示了它们的中心，与可塑性相关的功能，通常认为，原则上，它们的作用在其他哺乳动物物种中是保守的，包括灵长类动物和人类。总体而言，这很可能是正确的。但是，活动驱动的基因表达程序在物种之间并不完全通用，也不完全相同。例如，最近已经显示，人类神经元中突触活动打开的少数基因在啮齿动物中没有直系同源物。脱颖而出的基因之一是长期的非编码RNA基因Linc00473，这是一种灵长类动物特异性的基因，在人类神经元中突触活性迅速且尤其强烈地上调。但是，正如缺乏小鼠对应物的基因所预期的那样，其神经元中其功能没有表征。由于认知功能需要活动驱动的基因表达程序，因此我们假设Linc00473可能影响了导致人类的谱系中脑功能的演变。我们的初步数据表明，具有LINC00473表达的小鼠神经元的人性化会影响与可塑性相关的过程，这与我们的假设一致。在该项目中，我们建议在培养和体内小鼠中使用功能获得的实验，以及与人IPS细胞衍生的神经元的功能丧失方法研究灵长类动物特异性基因，Linc00473，Linc00473对神经元形态学，胞内信号的机制，基因范围和电子属性，以及层次，以及层次的属性。将进行行为研究，以检查通过扩展小鼠转录组，具有杰出的灵长类动物特异性，活性反应基因会影响认知性能。 LINC00473在神经元中的功能的识别可能揭示了已参与推动人类认知能力进化增强的机制。