Genomic flexibility and diversity in the brain: implications in neurological and psychiatric disorders
Our brains are very complex and plastic in term of cell composition, circuitry maturation and compensation, and behaviors (Fig. 1). Genomic flexibility and diversity provide our brains the opportunities to perform such demanding tasks. Two biological phenomena contributes to genomic flexibility and diversity: genomic imprinting (基因組印記) and RNA alternative splicing (RNA選擇性剪接). Dysfunctions of both phenomena contribute to neurological and psychiatric disorders. Therefore, it is very important to understand the role of both phenomena in the brain.
Role of genomic imprinting in neurological and psychiatric disorders
Genomic imprinting is an epigenetic mechanism through which genes are expressed in a parent-of-origin-specific manner (Fig. 2). Genomic imprinting predominantly occurs in the brain and dysfunction of genomic imprinting contributes to various neurological and psychiatric disorders (Fig. 3). Despite of the importance of genomic imprinting in the brain, the role of genomic imprinting remains largely unknown in the brain. To address this critical question, we comprehensively profiled imprinted genes in the mouse visual systems with a genome-wide scale. We identified novel underlying mechanisms of genomic imprinting in the brain. Those studies increase our understanding about how brain develops genomic imprinting and provides potential therapeutic strategies for brain disorders with dysfunctional imprinted genes.
Role of alternative splicing in neurological and psychiatric disorders
RNA alternative splicing generates diverse gene isoforms within limited number of genes. It creates bio-diversity of proteins. Besides genomic imprinting, we are also interested in the role of RNA splicing regulator in the brain. We specifically focused on one of RNA splicing regulators, RBFOX3 (Fig. 4). RBFOX3 mutations are linked to epilepsy and cognitive impairments (Fig. 5), but the underlying pathophysiology of these disorders is poorly understood. Here we report replication of human symptoms in a mouse model with disrupted Rbfox3 (Fig. 6). Rbfox3 knockout mice displayed increased seizure susceptibility and decreased anxiety-related behaviors. Focusing on hippocampal phenotypes, we found Rbfox3 knockout mice showed increased expression of plasticity genes Egr4 and Arc, and the synaptic transmission and plasticity were defective in the mutant perforant pathway (Fig. 7-9). The mutant dentate granules cells exhibited an increased frequency, but normal amplitude, of excitatory synaptic events, and this change was associated with an increase in the neurotransmitter release probability and dendritic spine density. Together, our results demonstrate anatomical and functional abnormality in Rbfox3 knockout mice, and may provide mechanistic insights for RBFOX3-related human brain disorders (Wang HY, et. al., Sci. Rep. 2015).