| 1 | PLoS ONE 2012 -1 7: e44017 |
|---|---|
| PMID | 22952857 |
| Title | Allele-biased expression in differentiating human neurons: implications for neuropsychiatric disorders. |
| Abstract | Stochastic processes and imprinting, along with genetic factors, lead to monoallelic or allele-biased gene expression. Stochastic monoallelic expression fine-tunes information processing in immune cells and the olfactory system, and imprinting plays an important role in development. Recent studies suggest that both stochastic events and imprinting may be more widespread than previously considered. We are interested in allele-biased gene expression occurring in the brain because parent-of-origin effects suggestive of imprinting appear to play a role in the transmission of schizophrenia (SZ) and autism spectrum disorders (ASD) in some families. In addition, allele-biased expression could help explain monozygotic (MZ) twin discordance and reduced penetrance. The ability to study allele-biased expression in human neurons has been transformed with the advent of induced pluripotent stem cell (iPSC) technology and next generation sequencing. Using transcriptome sequencing (RNA-Seq) we identified 801 genes in differentiating neurons that were expressed in an allele-biased manner. These included a number of putative SZ and ASD candidates, such as A2BP1 (RBFOX1), ERBB4, NLGN4X, NRG1, NRG3, NRXN1, and NLGN1. Overall, there was a modest enrichment for SZ and ASD candidate genes among those that showed evidence for allele-biased expression (chi-square, p = 0.02). In addition to helping explain MZ twin discordance and reduced penetrance, the capacity to group many candidate genes affecting a variety of molecular and cellular pathways under a common regulatory process - allele-biased expression - could have therapeutic implications. |
| SCZ Keywords | schizophrenia |
| 2 | Mol Autism 2015 -1 6: 56 |
| PMID | 26500751 |
| Title | Role of the cytoplasmic isoform of RBFOX1/A2BP1 in establishing the architecture of the developing cerebral cortex. |
| Abstract | RBFOX1 (also known as FOX1 or A2BP1) regulates alternative splicing of a variety of transcripts crucial for neuronal functions. Physiological significance of RBFOX1 during brain development is seemingly essential since abnormalities in the gene cause autism spectrum disorder (ASD) and other neurodevelopmental and neuropsychiatric disorders such as intellectual disability, epilepsy, attention deficit hyperactivity disorder, and schizophrenia. RBFOX1 was also shown to serve as a "hub" in ASD gene transcriptome network. However, the pathophysiological significance of RBFOX1 gene abnormalities remains to be clarified. To elucidate the pathophysiological relevance of RBFOX1, we performed a battery of in vivo and in vitro analyses of the brain-specific cytoplasmic isoform, RBFOX1-iso2, during mouse corticogenesis. In vivo analyses were based on in utero electroporation, and the role of RBFOX1-iso2 in cortical neuron migration, neurogenesis, and morphology was investigated by morphological methods including confocal laser microscope-assisted time-lapse imaging. In vitro analyses were carried out to examine the morphology of primary cultured mouse hippocampal neurons. Silencing of RBFOX1-iso2 in utero caused defects in the radial migration and terminal translocation of cortical neurons during corticogenesis. Time-lapse imaging revealed that radial migration was apparently impaired by dysregulated nucleokinesis. RBFOX1-iso2 also regulated neuronal network formation in vivo since axon extension to the opposite hemisphere and dendritic arborization were hampered by the knockdown. In in vitro analyses, spine density and mature spine number were reduced in RBFOX1-iso2-deficient hippocampal neurons. Impaired RBFOX1-iso2 function was found to cause abnormal corticogenesis during brain development. The abnormal process may underlie the basic pathophysiology of ASD and other neurodevelopmental disorders and may contribute to the emergence of the clinical symptoms of the patients with RBFOX1 gene abnormalities. |
| SCZ Keywords | schizophrenia |
| 3 | Sci Rep 2016 -1 6: 25671 |
| PMID | 27164557 |
| Title | Genetic Relationship between Schizophrenia and Nicotine Dependence. |
| Abstract | It is well known that most schizophrenia patients smoke cigarettes. There are different hypotheses postulating the underlying mechanisms of this comorbidity. We used summary statistics from large meta-analyses of plasma cotinine concentration (COT), Fagerström test for nicotine dependence (FTND) and schizophrenia to examine the genetic relationship between these traits. We found that schizophrenia risk scores calculated at P-value thresholds of 5?×?10(-3) and larger predicted FTND and cigarettes smoked per day (CPD), suggesting that genes most significantly associated with schizophrenia were not associated with FTND/CPD, consistent with the self-medication hypothesis. The COT risk scores predicted schizophrenia diagnosis at P-values of 5?×?10(-3) and smaller, implying that genes most significantly associated with COT were associated with schizophrenia. These results implicated that schizophrenia and FTND/CPD/COT shared some genetic liability. Based on this shared liability, we identified multiple long non-coding RNAs and RNA binding protein genes (DA376252, BX089737, LOC101927273, LINC01029, LOC101928622, HY157071, DA902558, RBFOX1 and TINCR), protein modification genes (MANBA, UBE2D3, and RANGAP1) and energy production genes (XYLB, MTRF1 and ENOX1) that were associated with both conditions. Further analyses revealed that these shared genes were enriched in calcium signaling, long-term potentiation and neuroactive ligand-receptor interaction pathways that played a critical role in cognitive functions and neuronal plasticity. |
| SCZ Keywords | schizophrenia |