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Members of the COE family of transcription factors are required for central nervous system (CNS) development. However, the function of COE in the post-embryonic CNS remains largely unknown. An excellent model for investigating gene function in the adult CNS is the freshwater planarian. This animal is capable of regenerating neurons from an adult pluripotent stem cell population and regaining normal function. We previously showed that planarian  coe  is expressed in differentiating and mature neurons and that its function is required for proper CNS regeneration. Here, we show that  coe  is essential to maintain nervous system architecture and patterning in intact (uninjured) planarians. We took advantage of the robust phenotype in intact animals to investigate the genetic programs  coe  regulates in the CNS. We compared the transcriptional profiles of control and  coe  RNAi planarians using RNA sequencing and identified approximately 900 differentially expressed genes in  coe  knockdown animals, including 397 downregulated genes that were enriched for nervous system functional annotations. Next, we validated a subset of the downregulated transcripts by analyzing their expression in  coe -deficient planarians and testing if the mRNAs could be detected in  coe +   cells. These experiments revealed novel candidate targets of  coe  in the CNS such as ion channel, neuropeptide, and neurotransmitter genes. Finally, to determine if loss of any of the validated transcripts underscores the  coe  knockdown phenotype, we knocked down their expression by RNAi and uncovered a set of  coe- regulated genes implicated in CNS regeneration and patterning, including orthologs of  sodium channel alpha-subunit  and  pou4 . Our study broadens the knowledge of gene expression programs regulated by COE that are required for maintenance of neural subtypes and nervous system architecture in adult animals.

COE Loss-of-Function Analysis Reveals a Genetic Program Underlying Maintenance and Regeneration of the Nervous System in Planarians