Independent control of functional rewiring after axon injury by <i>let-7</i> miRNA and insulin/insulin-like growth factor signaling pathways.

The capability of neurons to regenerate after injury becomes poor in adulthood. Previous studies indicated that loss of either <i>let-7</i> miRNA or components of insulin/insulin-like growth factor signaling (IIS) can overcome age-related decline in axon regeneration in <i>Caenorhabditis elegans</i>. In this study, we wanted to understand the relationship between these two pathways in axon regeneration. We found that the simultaneous removal of <i>let-7</i> and the gene for insulin receptor <i>daf-2</i> in parallel increased functional recovery involving posterior touch sensation following axotomy of posterior lateral microtubule (PLM) neurons in adulthood. Conversely, the loss of <i>let-7</i> could bypass the regeneration block due to the loss of DAF-16, a transcriptional mediator of DAF-2. Similarly, the loss of <i>daf-2</i> could bypass the requirement of LIN-41, a transcriptional co-factor of the <i>let-7</i> pathway. Our analysis revealed that these two pathways independently control the targeting of the regenerating axon to the ventral nerve cord (VNC), which leads to functional recovery. The computational analysis of the gene expression data revealed that a large number of genes, their interacting modules, and hub genes under the <i>let-7</i> and IIS pathways are exclusive in nature. Our study highlights a potential to promote neurite regeneration by harnessing the independent gene expression program involving the <i>let-7</i> and IIS pathways.