The conserved ancestral signaling pathway from cilium to nucleus.

Many signaling molecules are localized to both the primary cilium and nucleus. Localization of specific transmembrane receptors and their signaling scaffold molecules in the cilium is necessary for correct physiological function. After a specific signaling event, signaling molecules leave the cilium, usually in the form of an endocytic vesicle scaffold, and move to the nucleus, where they dissociate from the scaffold and enter the nucleus to affect gene expression. This ancient pathway probably arose very early in eukaryotic evolution as the nucleus and cilium co-evolved. Because there are similarities in molecular composition of the nuclear and ciliary pores the entry and exit of proteins in both organelles rely on similar mechanisms. In this Hypothesis, we propose that the pathway is a dynamic universal cilia-based signaling pathway with some variations from protists to man. Everywhere the cilium functions as an important organelle for molecular storage of certain key receptors and selection and concentration of their associated signaling molecules that move from cilium to nucleus. This could also have important implications for human diseases such as Huntington disease.