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A Upf3b-mutant mouse model with behavioral and neurogenesis defects.
Molecular Psychiatry ( IF 11.0 ) Pub Date : 2018-Aug-01 , DOI: 10.1038/mp.2017.173
L Huang 1 , E Y Shum 1 , S H Jones 1 , C-H Lou 1 , J Chousal 1 , H Kim 1 , A J Roberts 2 , L A Jolly 3, 4 , J L Espinoza 1 , D M Skarbrevik 1 , M H Phan 1 , H Cook-Andersen 1 , N R Swerdlow 5 , J Gecz 3, 4 , M F Wilkinson 1, 6
Affiliation  

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.

中文翻译:

具有行为和神经发生缺陷的 Upf3b 突变小鼠模型。

无义介导的 RNA 衰变 (NMD) 是一种高度保守和选择性的 RNA 降解途径,它作用于 RNA 在特定环境中终止其阅读框。NMD 以组织特异性和发育控制的方式进行调节,增加了它影响发育事件的可能性。事实上,NMD 因子的丢失或消耗已被证明会破坏跨越系统发育规模的生物体的发育事件。在人类中,NMD 因子基因 UPF3B 的突变会导致智力障碍 (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) 密切相关。在这里,我们报告了携带无效 Upf3b 等位基因的小鼠的产生和表征。这些 Upf3b-null 小鼠表现出恐惧条件学习的缺陷,但没有空间学习。Upf3b-null 小鼠在前脉冲抑制 (PPI) 方面也存在严重缺陷,这是一种在 SCZ 和其他脑部疾病患者中通常缺乏的感觉运动门控测量。与它们的 PPI 和学习缺陷一致,来自 Upf3b-null 小鼠的皮质锥体神经元在体内表现出树突棘成熟不足。此外,来自 Upf3b 缺失小鼠的神经干细胞分化能力受损,需要长时间培养才能产生具有电活动的功能性神经元。额叶皮层的 RNA 测序 (RNAseq) 分析确定了 UPF3B 调节的 RNA,包括直接 NMD 目标转录本,该转录本编码在神经分化、成熟和疾病中具有已知功能的蛋白质。
更新日期:2017-10-11
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