Genetic Analysis of Toll-like Receptor Signaling in Development.
The nervous system of many animals contains neurons that sense CO2 and promote various behavioral responses to this environmental and internally-generated cue. The nematode species, C. elegans, possesses a pair of neurons called BAG that are intrinsically sensitive to CO2 and drive an avoidance behavior. Recent studies have found that BAG neurons require components of a Toll-like receptor (TLR) signaling pathway to properly differentiate. TLRs are important receptors for innate immunity in both mammals and insects. The C. elegans genome encodes only one TLR, tol-1, which operates in a pathway with p38 MAPK PMK-3, and the IkB homolog IKB-1 to promote the function of BAG neurons. To identify new genes that function in TLR signaling, a suppressor screen was conducted in which fifteen mutants that restored gene expression in TLR mutant BAG neurons were isolated. This indicates that a complex genetic pathway with many components acts either in or together with TLR signaling to regulate neuronal differentiation. Two non-complementing mutations, wz75 and wz76, were mapped and the affected gene was cloned using Illumina-based whole-genome sequencing. These experiments identified the gene unc-31 as a suppressor of pmk-3, which encodes a MAP kinase downstream of TLR. Based on its known role in neuropeptide signaling, unc-31 likely regulates gene expression of BAG cells through a neuropeptide signal, as data suggests an unexpected link between TLR signaling, neuropeptides and neuronal differentiation.