HLH-3 is a C. elegans Achaete/Scute protein required for differentiation of the hermaphrodite-specific motor neurons.

Basic helix-loop-helix (bHLH) proteins of the Achaete/Scute (Ac/Sc) family are required for neurogenesis in both Drosophila and vertebrates. These transcription factors are commonly referred to as 'proneural' factors, as they promote neural fate in many contexts. Although Ac/Sc proteins have been studied in Hydra, jellyfish, many insects, and several vertebrates, the role of these proteins in Caenorhabditis elegans neurogenesis is relatively uncharacterized. The C. elegans genome consists of three Ac/Sc genes, previously identified as hlh-3, hlh-6, and hlh-14. Here, we characterize the role of hlh-3 in nervous system development. Although hlh-3 appears to be expressed in all neural precursors, we find that hlh-3 null mutants have a mostly functional nervous system. However, these mutants are egg-laying defective, resulting from a block in differentiation of the HSN motor neurons. Detectable HSNs have misdirected axon projection, which appears to result from a lack of netrin signaling within the HSNs. Thus, our findings suggest a novel link between Ac/Sc bHLH proteins and the expression of genes required for proper interpretation of axon guidance cues. Lastly, based on sequence identity, expression pattern, and a role in neural differentiation, hlh-3 is most likely an ortholog of Drosophila asense.