A Upf3b-mutant mouse model with behavioral and neurogenesis defects

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 (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 neuro-developmental disorders.

The Nonsense-Mediated mRNA Decay pathway degrades dendritically-targeted mRNAs to regulate long-term potentiation and cognitive function

“…Our data also provide comprehensive insight into the neuron-specific and spatiotemporal requirement for NMD in plasticity and behavior. Recently, a UPF3B null mutant mouse line was shown to have fear-conditioning defects but, unlike our observations in UPF2 conditional knockout mice, no spatial learning deficit [33]. There may be several reasons for this.…”

“…Despite its putative link to many mental disorders including autism and schizophrenia [27][28][29][30][31][32], whether NMD is relevant to the synaptic pathology and behavioral deficits of these diseases remains unclear. A recent study showed that UPF3B-null mice exhibit deficits in fear-conditioned learning, supporting a role for NMD in regulating synaptic plasticity and cognition [33]. However, because NMD is ubiquitous and required for neuronal differentiation [34], disruption of this pathway during development hinders determining the direct role of NMD in these processes.…”

A micro RNA cluster in the Fragile‐X region expressed during spermatogenesis targets FMR 1

“…Our long-term interest in miRNAs, X-linked gene clusters, and intellectual disability [27][28][29][30][31] led us to note the existence of a large group of miRNAs in the Fragile-X region of the mouse X chromosome ( Fig 1A). The Fragile-X region is best known for housing the FMR1 gene, which when mutated, causes Fragile-X Syndrome (FXS), the most common form of inherited intellectual disability in humans [32][33][34].…”

Targeting Translation Termination Machinery with Antisense Oligonucleotides for Diseases Caused by Nonsense Mutations

“…Further evaluation revealed that the variation in efficacy corresponded with the level of CF transmembrane conductance regulator (CFTR) mRNA, leading to the discovery that the efficiency of NMD might vary in these patients and hence affect the response to read-through treatments [53,54]. We previously demonstrated that inhibition of NMD by ASOmediated reduction of a branch-specific NMD factor, Upf3b [55,56], significantly stabilized hFIX mRNA harboring an early nonsense mutation (R29X) and significantly improved the efficacy of read-through therapy in this mouse hemophilia model [57]. These results underlined the need for a safe and effective read-through therapy and suggested that a combination strategy to simultaneously modulate both the NMD pathway and translation termination process is required to treat genetic diseases caused by nonsense mutations.…”