| 1 | Mol. Psychiatry 2011 Mar 16: 238-9 |
|---|---|
| PMID | 20479756 |
| Title | A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia |
| 2 | Psychiatr. Genet. 2012 Jun 22: 150-1 |
| PMID | 21862950 |
| Title | A nonconservative amino acid change in the UPF3B gene in a patient with schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia |
| 3 | Curr. Mol. Med. 2013 Jul 13: 887-99 |
| PMID | 23638902 |
| Title | An EJC factor RBM8a regulates anxiety behaviors. |
| Abstract | Neuroplasticity depends on the precise timing of gene expression, which requires accurate control of mRNA stability and rapid elimination of abnormal mRNA. Nonsense-mediated mRNA decay (NMD) is an RNA surveillance mechanism that ensures the speedy degradation of mRNAs carrying premature termination codons (PTCs). This mechanism relies on several key Exon Junction Complex (EJC) factors to distinguish PTCs from normal stop codons. NMD degrades not only aberrant transcripts carrying PTCs, but also normal transcripts harboring a normal stop codon [1]. Intriguingly, mutations in an NMD factor, UPF3B, have been found in patients with autism [2, 3]. A binding partner of UPF3B, RBM8a, is located in the 1q21.1 copy-number variation (CNV) associated with mental retardation, autism [4], schizophrenia [5], and microcephaly [6]. However, the functions of EJC factors and their roles in behavioral regulation are still elusive. RBM8a protein is a core component of the EJC that plays an important role in NMD. Recent genetic study indicated that RBM8a gain-of-function significantly associated with intellectual disability [7]. In this study we investigated the effect of RBM8a overexpression on affective behaviors in mice. Lentivirus expressing RBM8a was infused into the hippocampus of adult mice to conduct behavioral studies including social interaction, open field, elevated plus maze, and forced swimming tests. Our results showed that overexpression of RBM8a in the mouse dentate gyrus (DG) leads to increased anxiety-like behavior, abnormal social interaction and decreased immobile time in forced swimming test (FST). To examine the underlying mechanism, we found that overexpressing RBM8a in cultured primary neurons lead to significant higher frequency of miniature excitatory postsynaptic currents (mEPSCs). To explore the underlying mechanism of RBM8a mediated behavioral changes, RNA-immunoprecipitation (RNA-IP) detected that RBM8a binds to CaMK2, GluR1 and Egr1 mRNA, suggesting that RBM8a may target neuronal genes to regulate behaviors. This is the first study that demonstrates the key role of RBM8a on the emotional behaviors in mice. These results reveal new neural mechanisms by which NMD modulates behaviors and potentially provide a better understanding of pathophysiology underlying psychiatric disorders. |
| SCZ Keywords | schizophrenia |
| 4 | Hum. Mol. Genet. 2013 Dec 22: 4673-87 |
| PMID | 23821644 |
| Title | The UPF3B gene, implicated in intellectual disability, autism, ADHD and childhood onset schizophrenia regulates neural progenitor cell behaviour and neuronal outgrowth. |
| Abstract | Loss-of-function mutations in UPF3B result in variable clinical presentations including intellectual disability (ID, syndromic and non-syndromic), autism, childhood onset schizophrenia and attention deficit hyperactivity disorder. UPF3B is a core member of the nonsense-mediated mRNA decay (NMD) pathway that functions to rapidly degrade transcripts with premature termination codons (PTCs). Traditionally identified in thousands of human diseases, PTCs were recently also found to be part of 'normal' genetic variation in human populations. Furthermore, many human transcripts have naturally occurring regulatory features compatible with 'endogenous' PTCs strongly suggesting roles of NMD beyond PTC mRNA control. In this study, we investigated the role of UPF3B and NMD in neural cells. We provide evidence that suggests UPF3B-dependent NMD (UPF3B-NMD) is regulated at multiple levels during development including regulation of expression and sub-cellular localization of UPF3B. Furthermore, complementary expression of UPF3B, Upf3a and Stau1 stratify the developing dorsal telencephalon, suggesting that alternative NMD, and the related Staufen1-mediated mRNA decay (SMD) pathways are differentially employed. A loss of UPF3B-NMD in neural progenitor cells (NPCs) resulted in the expansion of cell numbers at the expense of their differentiation. In primary hippocampal neurons, loss of UPF3B-NMD resulted in subtle neurite growth effects. Our data suggest that the cellular consequences of loss of UPF3B-NMD can be explained in-part by changes in expression of key NMD-feature containing transcripts, which are commonly deregulated also in patients with UPF3B mutations. Our research identifies novel pathological mechanisms of UPF3B mutations and at least partly explains the clinical phenotype of UPF3B patients. |
| SCZ Keywords | schizophrenia |
| 5 | Mol Brain 2015 -1 8: 33 |
| PMID | 26012578 |
| Title | Full UPF3B function is critical for neuronal differentiation of neural stem cells. |
| Abstract | Mutation in the UPF3B gene on chromosome X is implicated in neurodevelopmental disorders including X-linked intellectual disability, autism and schizophrenia. The protein UPF3B is involved in the nonsense-mediated mRNA decay pathway (NMD) that controls mRNA stability and functions in the prevention of the synthesis of truncated proteins. Here we show that NMD pathway components UPF3B and UPF1 are down-regulated during differentiation of neural stem cells into neurons. Using tethered function assays we found that UPF3B missense mutations described in families with neurodevelopmental disorders reduced the activity of UPF3B protein in NMD. In neural stem cells, UPF3B protein was detected in the cytoplasm and in the nucleus. Similarly in neurons, UPF3B protein was detected in neurites, the somatic cytoplasm and in the nucleus. In both cell types nuclear UPF3B protein was enriched in the nucleolus. Using GFP tagged UPF3B proteins we found that the missense mutations did not affect the cellular localisation. Expression of missense mutant UPF3B disturbed neuronal differentiation and reduced the complexity of the branching of neurites. Neuronal differentiation was similarly affected in the presence of the NMD inhibitor Amlexanox. The expression of mutant UPF3B proteins lead to a subtle increase in mRNA levels of selected NMD targets. Together our findings indicate that, despite the down-regulation of NMD factors, functional NMD is critical for neuronal differentiation. We propose that the neurodevelopmental phenotype of UPF3B missense mutation is caused by impairment of NMD function altering neuronal differentiation. |
| SCZ Keywords | schizophrenia |