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A Upf3b-mutant mouse model with behavioral and neurogenesis defects

Molecular Psychiatry volume 23, pages 1773–1786 (2018)Cite this article

Abstract

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.

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Acknowledgments

This research was supported by National Institutes of Health grants GM111838 (MFW), MH59803 (NRS), MH94320 (NRS), T32 EB00938008 (SJ), as well as a Howard Hughes Medical Institute international fellow award (ES), a Distinguished Investigator Award from the Brain & Behavior Research Foundation (NRS) and a National Health & Medical Research Council grant APP1063808 (JG, MFW and LJ), and the Australian Research Council Discovery Early Career Research Award DE160100620 (LJ). We are grateful to Dr. Martin Marsala (UCSD) and Marián Hruška-Plocháň (UCSD) for helping with mNSC isolation, mNSC differentiation and electrophysiology recordings. We also thank Kristin Jepsen and the IGM Genomics Center, University of California, San Diego, La Jolla, CA, for performing RNAseq analyses.

Author information

Author notes

  1. Current address: Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA.

  2. Current address: City of Hope – Beckman Research Institute, Duarte, CA, USA.

  3. Current address: J Craig Venter Institute, La Jolla, CA, USA.

Authors and Affiliations

  1. Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA

    L Huang, E Y Shum, S H Jones, C-H Lou, J Chousal, H Kim, J L Espinoza, D M Skarbrevik, M H Phan, H Cook-Andersen & M F Wilkinson

  2. Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA, USA

    A J Roberts

  3. Adelaide Medical School and Robison Research Institute, University of Adelaide, Adelaide, SA, Australia

    L A Jolly & J Gecz

  4. South Australian Health and Medical Research Institute, Adelaide, SA, Australia

    L A Jolly & J Gecz

  5. Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA

    N R Swerdlow

  6. Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA, USA

    M F Wilkinson

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Correspondence to M F Wilkinson.

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Huang, L., Shum, E.Y., Jones, S.H. et al. A Upf3b-mutant mouse model with behavioral and neurogenesis defects. Mol Psychiatry 23, 1773–1786 (2018). https://doi.org/10.1038/mp.2017.173

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