The carboxyl-terminal binding protein-1 (CTBP-1) can function in the nervous system to regulate longevity, gene expression and axon guidance

Abstract

C-terminal binding proteins (CtBPs) are recruited by a variety of transcription factors to mediate gene repression. C. elegans 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 found that expressing CTBP-1 solely in the nervous system of a ctbp-1 mutant significantly reduced lips-7 transcription. Locomotory behaviours such as exploration behaviour are regulated by a neuronal circuit involving many subtypes of neurons and incorrect development or function of these neurons results in changes in these behaviours. We observed reduced exploration behaviour in ctbp-1 mutants. Our examination of a subset of neurons involved in regulating locomotion, among which are the dorsal SMD (SMDD) neurons, revealed that SMDD axons are misguided in ctbp-1 mutants. Expressing CTBP-1 under the control of the endogenous ctbp-1 promoter rescued the SMDD axon guidance defect in ctbp-1 mutants. Additional rescue experiments suggest that CTBP-1 functions in the nervous system to regulate SMDD axon guidance. Interestingly, the pre-synaptic marker RAB-3 was found to localise to the misguided portion of SMDD axons in a ctbp-1 mutant. In summary, our findings show that CTBP-1 can function in the nervous system to regulate longevity, gene expression and axon guidance.