Proteins that control the geometry of ciliary ends
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Microtubules are cytoskeletal polymers that are inherently dynamic, switching between phases of elongation and shrinkage. Their dynamic behavior is tightly regulated in order to create organized groups and networks of microtubules that perform diverse cellular functions. One of the most complex microtubule organizations is found in cilia, organelles containing an axoneme core made of nine radially arranged compound (fused wall) microtubules. For most of their length these compound microtubules have a doublet conformation and are composed of a complete A-tubule and an incomplete B-tubule. However, in all cilia studied to date, the B-tubules are shorter than A-tubules giving rise to two main longitudinal compartments of the axoneme; the middle segment (in which the outer microtubules have both the A and B-tubule) and the distal segment (in which the outer microtubules have only the A-tubule extensions). The middle and distal axoneme segment have different functions. The middle segment drives ciliary motility while the distal segment is the side of cilium assembly and signaling in sensory cilia. The existence of longitudinal compartments in the cilium relies on the precise regulation of the termination points of A and B-tubules. Therefore, cilia provide a good opportunity to study how microtubules differentiate within the same functional network. The aim of this study was to explore the mechanisms that regulate the geometry of the distal segment in cilia and determine if this structural organization serves a particular function. We discovered that the plus-ends of complete (A-tubules) and incomplete (B-tubules) microtubules in cilia are biochemically distinct. We show that FAP256/CEP104 protein localizes to the ends of complete microtubules and promotes their polymerization whereas CHE-12/Crescerin and ARMC9 proteins localize to the ends of B-tubules where they promote their polymerization and depolymerization, respectively. Changes in the length of microtubule subtypes affect the geometry of the distal segment, which correlates with defects in the motile and sensory functions of cilia. Importantly, mutation in FAP256/CEP104 and ARMC9 cause Joubert syndrome, a severe neurological developmental disorder, and our results suggest that defects in distal segment geometry may underlie the disease pathology.