C-terminal binding proteins (CtBPs) are transcriptional co-repressors that are conserved across many species, including Caenorhabditis elegans. C. elegans CTBP-1 is expressed in the nervous system and hypodermis, and regulates several processes, including lifespan. We previously identified abnormal axonal morphology of dorsal SMD (SMDD) neurons in developing and adult
ctbp-1 mutant animals, highlighting a role for CTBP-1 in the development and maintenance of the nervous system. Further characterisation of SMDD axonal morphology revealed that
ctbp-1 mutant animals display longer axons than wild-type, suggesting that axon guidance and/or termination cues are disrupted. From the single C. elegans
ctbp-1 locus, two isoforms are transcribed:
ctbp-1a and
ctbp-1b. These transcripts encode distinct proteins: CTBP-1a, which contains an additional Thanatos-associated protein (THAP) domain, and the shorter CTBP-1b which does not house this domain. Using mutations that affect one or both isoforms, we found that CTBP-1a and not CTBP-1b is required for regulation of SMDD development and maintenance. To understand the mechanism by which CTBP-1 influences SMDD development, we performed epistasis experiments with known regulators of axon guidance and maintenance. We found that CTBP-1 functions independently from the SMD axon guidance pathway regulated by the L1 cell adhesion molecule LAD-2. Epistasis experiments were also performed to assess the roles of putative CTBP-1-target genes in SMDD development. Putative target genes were identified from a microarray dataset by misregulated expression in a
ctbp-1 mutant background, including the L1 cell adhesion molecule SAX-7. We found that loss of SAX-7 short isoforms in a
ctbp-1 mutant background reduces SMDD axon defects. These findings reveal distinct regulatory pathways that define parallel roles for SAX-7 and LAD-2 in SMDD axon development.