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RNA-Sequencing Analysis Reveals a Regulatory Role for Transcription Factor Fezf2 in the Mature Motor Cortex.

ABSTRACT: Forebrain embryonic zinc finger (Fezf2) encodes a transcription factor essential for the specification of layer 5 projection neurons (PNs) in the developing cerebral cortex. As with many developmental transcription factors, Fezf2 continues to be expressed into adulthood, suggesting it remains crucial to the maintenance of neuronal phenotypes. Despite the continued expression, a function has yet to be explored for Fezf2 in the PNs of the developed cortex. Here, we investigated the role of Fezf2 in mature neurons, using lentiviral-mediated delivery of a shRNA to conditionally knockdown the expression of Fezf2 in the mouse primary motor cortex (M1). RNA-sequencing analysis of Fezf2-reduced M1 revealed significant changes to the transcriptome, identifying a regulatory role for Fezf2 in the mature M1. Kyoto Encyclopedia Genes and Genomes (KEGG) pathway analyses of Fezf2-regulated genes indicated a role in neuronal signaling and plasticity, with significant enrichment of neuroactive ligand-receptor interaction, cell adhesion molecules and calcium signaling pathways. Gene Ontology analysis supported a functional role for Fezf2-regulated genes in neuronal transmission and additionally indicated an importance in the regulation of behavior. Using the mammalian phenotype ontology database, we identified a significant overrepresentation of Fezf2-regulated genes associated with specific behavior phenotypes, including associative learning, social interaction, locomotor activation and hyperactivity. These roles were distinct from that of Fezf2-regulated genes identified in development, indicating a dynamic transition in Fezf2 function. Together our findings demonstrate a regulatory role for Fezf2 in the mature brain, with Fezf2-regulated genes having functional roles in sustaining normal neuronal and behavioral phenotypes. These results support the hypothesis that developmental transcription factors are important for maintaining neuron transcriptomes and that disruption of their expression could contribute to the progression of disease phenotypes.

SUBMITTER: Clare AJ

PROVIDER: S-EPMC5594072 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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RNA-Sequencing Analysis Reveals a Regulatory Role for Transcription Factor Fezf2 in the Mature Motor Cortex.

Clare Alison J AJ Wicky Hollie E HE Empson Ruth M RM Hughes Stephanie M SM

Frontiers in molecular neuroscience 20170907

Forebrain embryonic zinc finger (Fezf2) encodes a transcription factor essential for the specification of layer 5 projection neurons (PNs) in the developing cerebral cortex. As with many developmental transcription factors, Fezf2 continues to be expressed into adulthood, suggesting it remains crucial to the maintenance of neuronal phenotypes. Despite the continued expression, a function has yet to be explored for Fezf2 in the PNs of the developed cortex. Here, we inve ...[more]

PMID: 28936162

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Project description:Background and Purpose- Many restorative therapies have been used to study brain repair after stroke. These therapeutic-induced changes have revealed important insights on brain repair and recovery mechanisms; however, the intrinsic changes that occur in spontaneously recovery after stroke is less clear. The goal of this study is to elucidate the intrinsic changes in spontaneous recovery after stroke, by directly investigating the transcriptome of primary motor cortex in mice that naturally recovered after stroke. Methods- Male C57BL/6J mice were subjected to transient middle cerebral artery occlusion. Functional recovery was evaluated using the horizontal rotating beam test. A novel in-depth lesion mapping analysis was used to evaluate infarct size and locations. Ipsilesional and contralesional primary motor cortices (iM1 and cM1) were processed for RNA-sequencing transcriptome analysis. Results- Cluster analysis of the stroke mice behavior performance revealed 2 distinct recovery groups: a spontaneously recovered and a nonrecovered group. Both groups showed similar lesion profile, despite their differential recovery outcome. RNA-sequencing transcriptome analysis revealed distinct biological pathways in the spontaneously recovered stroke mice, in both iM1 and cM1. Correlation analysis revealed that 38 genes in the iM1 were significantly correlated with improved recovery, whereas 74 genes were correlated in the cM1. In particular, ingenuity pathway analysis highlighted the involvement of cAMP signaling in the cM1, with selective reduction of Adora2a (adenosine receptor A2A), Drd2 (dopamine receptor D2), and Pde10a (phosphodiesterase 10A) expression in recovered mice. Interestingly, the expressions of these genes in cM1 were negatively correlated with behavioral recovery. Conclusions- Our RNA-sequencing data revealed a panel of recovery-related genes in the motor cortex of spontaneously recovered stroke mice and highlighted the involvement of contralesional cortex in spontaneous recovery, particularly Adora2a, Drd2, and Pde10a-mediated cAMP signaling pathway. Developing drugs targeting these candidates after stroke may provide beneficial recovery outcome.

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RNA-Sequencing Analysis Reveals a Regulatory Role for Transcription Factor Fezf2 in the Mature Motor Cortex.

Publications

RNA-Sequencing Analysis Reveals a Regulatory Role for Transcription Factor <i>Fezf2</i> in the Mature Motor Cortex.

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