Generation and Maintenance of Motor Neuron Identity Through the Intersection of HOX/PBX and Terminal Selector Functions

Animals rely on many different types of motor neurons to generate precise and flexible movements, but how these neuron subtypes are specified remains an open question. Here, we examine how the highly conserved family of developmental genes called Hox genes, together with their cofactors, help define distinct spatial motor neuron identities in the nervous system of the nematode Caenorhabditis elegans. We find that different Hox genes act in specific anteroposterior regions of the ventral nerve cord to either positively or negatively regulate motor neuron terminal identity genes. First, in anterior motor neurons, certain Hox genes work together with a cofactor called PBX and a neuron-type-specific regulator (UNC-3) to activate genes required for proper motor neuron function. Second, a posterior midbody Hox gene suppresses these genes in posterior midbody neurons, while a more posterior Hox gene activates a unique set of genes in lumbar motor neurons through a different mechanism. Third, we show that some Hox genes and PBX are needed not only during early development but also later in life to maintain motor neuron identity. Together, our findings reveal how combinations of Hox genes and cofactors generate and preserve motor neuron diversity across the anterior-posterior axis, providing insight into general principles of nervous system development.