Clare Alison J, Wicky Hollie E, Empson Ruth M, Hughes Stephanie M
Department of Biochemistry, School of Biomedical Sciences, University of OtagoDunedin, New Zealand.
Brain Health Research Centre, University of OtagoDunedin, New Zealand.
Front Mol Neurosci. 2017 Sep 7;10:283. doi: 10.3389/fnmol.2017.00283. eCollection 2017.
() 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, 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 in the PNs of the developed cortex. Here, we investigated the role of in mature neurons, using lentiviral-mediated delivery of a shRNA to conditionally knockdown the expression of in the mouse primary motor cortex (M1). RNA-sequencing analysis of -reduced M1 revealed significant changes to the transcriptome, identifying a regulatory role for in the mature M1. Kyoto Encyclopedia Genes and Genomes (KEGG) pathway analyses of -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 -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 -regulated genes associated with specific behavior phenotypes, including associative learning, social interaction, locomotor activation and hyperactivity. These roles were distinct from that of -regulated genes identified in development, indicating a dynamic transition in function. Together our findings demonstrate a regulatory role for in the mature brain, with -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.
（）编码一种转录因子，该转录因子对于发育中的大脑皮层第5层投射神经元（PNs）的特化至关重要。与许多发育转录因子一样，其在成年期仍持续表达，这表明它对于维持神经元表型仍然至关重要。尽管持续表达，但在发育成熟的皮层的PNs中，其功能尚未得到探索。在这里，我们使用慢病毒介导的短发夹RNA（shRNA）递送，有条件地敲低小鼠初级运动皮层（M1）中（）的表达，以研究其在成熟神经元中的作用。对（）表达降低的M1进行RNA测序分析，揭示了转录组的显著变化，确定了其在成熟M1中的调节作用。对（）调控基因的京都基因与基因组百科全书（KEGG）通路分析表明其在神经元信号传导和可塑性方面发挥作用，神经活性配体-受体相互作用、细胞粘附分子和钙信号通路显著富集。基因本体分析支持（）调控基因在神经元传递中的功能作用，并额外表明其在行为调节中的重要性。使用哺乳动物表型本体数据库，我们确定了与特定行为表型相关的（）调控基因显著过度表达，包括联想学习、社交互动、运动激活和多动。这些作用与在发育过程中鉴定的（）调控基因的作用不同，表明（）功能存在动态转变。我们的研究结果共同证明了（）在成熟大脑中的调节作用，（）调控基因在维持正常神经元和行为表型方面具有功能作用。这些结果支持了这样的假设，即发育转录因子对于维持神经元转录组很重要，并且它们表达的破坏可能导致疾病表型的进展。
