Investigating the Role of Neuronal SKN-1 in C. elegans

In C. elegans, the SKN-1/Nrf transcription factor is a crucial component for controlling responses to oxidative stress, redox balance, proteostasis, healthy ageing and improving lifespan. SKN-1 has three major isoforms that function independently of one another. SKN-1A and SKN-1C are localised in the C. elegans intestine and have been extensively studied. The third isoform, SKN-1B, is confined to two amphid chemosensory neurons in the head of C. elegans and is still relatively unexplored. Here, we investigate the role of SKN-1B in three major pathways that all contribute to longevity; the insulin/IGF-1 signalling (IIS) pathway, the endoplasmic reticulum unfolded protein response (UPRer) and mitochondrial morphology. Publications investigating the longevity effects of dietary restriction (DR) have also uncovered evidence that may suggest SKN-1B has a role here, and so therefore we also include conditional DR by two published methods; bacterial deprivation (BD) and liquid DR (lDR). We found that SKN-1B is not required for induction of DAF-16 nuclear localisation or expression upon DR, however nuclear localisation in SKN-1B mutant worms is short-lived compared to wildtype. Interestingly also, SKN-1B is required for increased expression of the DAF-16-target gene sod-3 using the lDR protocol, but not in BD. It was also discovered that SKN-1B positively regulates hsp-4 expression under non-stressed conditions, but it was not required for induction of hsp-4 expression during ER stress caused by ero-1 RNAi. In addition, the long-lived phenotype of ero-1 RNAi does not require SKN-1B and therefore its only role may be in basal expression of UPRer components under normal conditions. Finally, we found that SKN-1B mutant worms exhibit a mitochondrial morphology defect characterised by an increased network fragmentation that resembles a starved phenotype. SKN-1B mutant worms have a normal N2 lifespan, and so this phenotype is of an unknown physiological consequence. This data together provides new insights into the role of the under-studied SKN-1B transcription factor which can hopefully offer new directions for investigation. It has been shown that SKN-1B has multiple complex roles in many signalling pathways through neuroendocrine modulation; this along with its emerging role in behaviour present an exciting new area of research.