The transcriptional repressor CTBP-1 functions in the nervous system of Caenorhabditis elegans to regulate lifespan

Abstract

C-terminal binding proteins (CtBPs) are recruited by a variety of transcription factors to mediate gene repression. Nematode CTBP-1 has previously been shown to play a role in the regulation of lifespan; Caenorhabditis elegans strains carrying a deletion in the ctbp-1 gene showed a 10–20% increase in mean and maximal lifespan compared with wild-type control strains. We set out to identify the tissues in which CTBP-1 functions to regulate lifespan in C. elegans. Our analysis of reporter genes shows that CTBP-1 is predominantly expressed in the nervous system with lower levels detectable in the hypodermis. Tissue-specific rescue experiments demonstrated that CTBP-1 functions in the nervous system to regulate lifespan. Previously, the lifespan extension in a ctbp-1 mutant was attributed, at least in part, to the misregulation of a lipase gene, lips-7. We therefore focussed on lips-7 and found that expressing CTBP-1 solely in the nervous system of a ctbp-1 mutant significantly reduced lips-7 transcription. In addition, we studied another ctbp-1 mutant allele that also displayed a long-lived phenotype. In this case, lips-7 expression was unaffected. This observation argues that, while lips-7 may play a role in lifespan, its de-repression is not essential for the extension of lifespan phenotype. We show that a prominent site of LIPS-7 expression is the hypodermis, one of the sites of fat storage in C. elegans. Interestingly, we did not observe co-localisation of CTBP-1 and lips-7 transcription in the nervous system, indicating that CTBP-1 may be acting indirectly, in a cell non-autonomous manner. In summary, our data confirm that CTBP-1 is involved in the regulation of lips-7 transcription but suggest that it may perform additional roles in the nervous system that contribute to the regulation of longevity.