Student Theses and Dissertations

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RU Laboratory

Bargmann Laboratory


protein transport, neuronal microtubules, C. elegans, UNC-33/CRMP, UNC-44, chemoreceptor ODR-10


Neurons are highly polarized cells, capable of receiving, processing and transmitting information, with the help of their specialized domains, an axon and one or more dendrites. The molecular dissimilarities between these domains are critical for neuronal function, and are a result of asymmetric trafficking of a large number of cellular components including ion channels, neurotransmitter receptors, synaptic vesicles, and signaling proteins. Yet, despite the significance of asymmetric protein transport in neuronal polarity, the molecules and mechanisms that direct polarized transport to axons, dendrites and cilia in neurons are only partly understood. In this thesis, I describe my effort at understanding how neuronal proteins are asymmetrically localized. I pursued a genetic approach, employing the C. elegans nervous system as an in vivo model system for protein transport to axons, dendrites and cilia. Having established a system to visualize axon-dendrite compartmentalization in PVD mechanosensory neurons, I identified the microtubule-binding protein UNC- 33/CRMP and the ankyrin homolog UNC-44 as major regulators of polarized protein transport in C. elegans neurons. In both unc-33 and unc-44 mutants, axonal proteins are distributed randomly between axons and dendrites, and dendritic proteins are partly mislocalized to axons. In both mutants, the axonal kinesin UNC-104/KIF1A actively misdelivers axonal proteins to both axons and dendrites. An altered distribution of neuronal microtubules in unc-33 and unc-44 mutants suggests that a primary defect in microtubule organization underlies defective protein targeting. unc-44 is required for UNC-33 localization to axons, where its enrichment in a proximal axonal segment suggests analogies with the vertebrate axon initial segment. In parallel experiments, I analyzed odr-8 mutants, which were previously identified in screens for chemotaxis-defective mutants and shown to affect GPCR localization. odr-8 mutants fail to localize a subset of odorant receptors including the ODR-10 diacetyl receptor to sensory cilia. I found that odr-8 encodes the C. elegans homolog of mammalian UfSP2, which acts as a cysteine-protease specific for UFM1, a ubiquitin-like molecule. ODR-10::GFP is retained in the ER in odr-8 mutants, whereas cilia localization of ODR-10::GFP is enhanced in ufm-1 mutants. ufm-1 function is required for ER retention of ODR-10::GFP in odr-8 animals. Thus, ODR-8 and UFM-1 may act antagonistically to regulate ER exit and cilia localization of chemoreceptors such as ODR-10.


A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

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