Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
Mol Psychiatry. 2018 Aug;23(8):1773-1786. doi: 10.1038/mp.2017.173. Epub 2017 Sep 26.
Nonsense-mediated RNA decay (NMD) is a highly conserved and selective RNA degradation pathway that acts on RNAs terminating their reading frames in specific contexts. NMD is regulated in a tissue-specific and developmentally controlled manner, raising the possibility that it influences developmental events. Indeed, loss or depletion of NMD factors have been shown to disrupt developmental events in organisms spanning the phylogenetic scale. In humans, mutations in the NMD factor gene, UPF3B, cause intellectual disability (ID) and are strongly associated with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia (SCZ). Here, we report the generation and characterization of mice harboring a null Upf3b allele. These Upf3b-null mice exhibit deficits in fear-conditioned learning, but not spatial learning. Upf3b-null mice also have a profound defect in prepulse inhibition (PPI), a measure of sensorimotor gating commonly deficient in individuals with SCZ and other brain disorders. Consistent with both their PPI and learning defects, cortical pyramidal neurons from Upf3b-null mice display deficient dendritic spine maturation in vivo. In addition, neural stem cells from Upf3b-null mice have impaired ability to undergo differentiation and require prolonged culture to give rise to functional neurons with electrical activity. RNA sequencing (RNAseq) analysis of the frontal cortex identified UPF3B-regulated RNAs, including direct NMD target transcripts encoding proteins with known functions in neural differentiation, maturation and disease. We suggest Upf3b-null mice serve as a novel model system to decipher cellular and molecular defects underlying ID and neurodevelopmental disorders.
无义介导的 RNA 降解（NMD）是一种高度保守且具有选择性的 RNA 降解途径，作用于在特定环境中终止其读码框的 RNA。NMD 的调控具有组织特异性和发育性控制，这使得它有可能影响发育事件。事实上，在跨越系统发生范围的生物体中，已经证明 NMD 因子的缺失或耗竭会破坏发育事件。在人类中，NMD 因子基因 UPF3B 的突变导致智力障碍（ID），并且与自闭症谱系障碍（ASD）、注意力缺陷多动障碍（ADHD）和精神分裂症（SCZ）强烈相关。在这里，我们报告了携带无效 Upf3b 等位基因的小鼠的产生和特征。这些 Upf3b 缺失小鼠在恐惧条件性学习中表现出缺陷，但在空间学习中没有表现出缺陷。Upf3b 缺失小鼠也存在前脉冲抑制（PPI）的严重缺陷，这是一种常见于 SCZ 和其他大脑障碍个体的感觉运动门控的衡量标准。与他们的 PPI 和学习缺陷一致，Upf3b 缺失小鼠的皮质锥体神经元在体内显示出树突棘成熟缺陷。此外，Upf3b 缺失小鼠的神经干细胞分化能力受损，需要延长培养才能产生具有电活动的功能性神经元。对前额皮质的 RNA 测序（RNAseq）分析鉴定了 UPF3B 调控的 RNA，包括编码已知在神经分化、成熟和疾病中具有功能的蛋白质的直接 NMD 靶转录本。我们建议 Upf3b 缺失小鼠可作为一种新型模型系统，用于破译 ID 和神经发育障碍的细胞和分子缺陷。
