SAVE THE DATE: Thesis Defense, Luis A. Martínez-Velázquez, 9/8 2pm, Skirball 4th floor seminar room

Tue, 09/05/2017 - 4:00am

Molecular genetics of trafficking to the sensory cilium
September 8, 2017
2:00 pm
Skirball 4th floor seminar room
PhD Candidate: Luis A. Martínez-Velázquez
Thesis Advisor: Niels Ringstad, PhD
Training Program: Neuroscience and Physiology
The primary cilium is a microtubule-based organelle specialized for cell signaling. Mutations that affect the generation and maintenance of the primary cilium are the root cause of a family of disorders that affect multiple organ systems, and are collectively referred to as ciliopathies. Defects caused by ciliopathies include situs-inversus, obesity, intellectual disability, polycystic kidney disease and sensory dysfunction such as anosmia and blindness. The sensory defects caused by ciliopathies highlight the important role of the primary cilium in sensory neurons, which use cilia to organize factors involved in sensory transduction. Despite the importance of cilia in sensory transduction, how proteins are targeted to these specialized membrane domains remains poorly understood. Sensory neurons of the nematode C. elegans offer an excellent model to use genetic analysis to determine mechanisms required for the generation, maintenance, and function of sensory cilia. Through studies of the chemosensory BAG neurons of C. elegans, I have identified the nematode homolog of a human retinal dystrophy gene of unknown function, RD3. I show that this gene encodes a Golgi-associated protein required for efficient trafficking of receptor-type guanylate cyclases to the sensory cilium. Furthermore, I use this model to identify mutations that restore cyclase trafficking to RD3 mutants. Suppressor mutations target key components of the retromer complex, which mediates recycling of cargo from endosomes to the Golgi. My data show that in sensory neurons there exists a critical balance between the rates of anterograde and retrograde trafficking of cargo destined for the sensory cilium, and that this balance requires a molecular specialization at an early stage of the secretory pathway. Finally, I show that this experimental model can be used to identify additional factors that likely promote the transport of cargo containing vesicles to the base of the sensory cilium and fusion to the ciliary membrane.