The human nervous system consists of thousands of cell types with distinct functions and patterns of gene expression. The mechanisms that generate this spectacular cellular diversity are only partially understood. The exceptional variety of neuronal cell types suggests that there might be unique developmental strategies in the nervous system that has not been discovered in other developmental systems. Understanding such mechanisms is of potential importance for understanding neurological and psychiatric diseases that result from disruption of neuronal development. In the olfactory system of C. elegans, a stochastic, coordinated cell signaling event initiated by axon contact causes two olfactory neurons to express different odorant receptor genes. The use of an axon interaction to generate olfactory neuronal diversity represents an unexpected developmental strategy. The nature of the initial signal on the axon, and its receptor, are unknown. A genetic approach followed by positional cloning will be used to identify the signal and the receptor. These molecules will then be studied genetically and molecularly to understand the developmental logic of this signaling event. The initial interaction between the two olfactory neurons triggers a novel-signaling pathway that includes an N/P-type calcium channel, the calcium/calmodulin dependent protein kinase CaMKII, and an ASK1/p38/JNK MAP kinase cascade. Calcium channels and CaMKII are well-characterized players in neuronal function, but the involvement of these proteins in neuronal diversification is unexpected. Thus excitable cells like neurons may use unconventional strategies to make developmental decisions. Additional genes in this pathway will be characterized, and proteins within the pathway analyzed, to learn how this signaling pathway is assembled and how it transmits a signal from the axon to the nucleus in order to affect neuronal development. Mammalian CamKII and ASK1 kinases have been implicated in neurological seizures and neurodegenerative responses to insult. Characterizing these signaling pathways may elucidate related pathways that are important in disease and injury states.
