The coordination of behavior and physiology by the nervous system is complex, requiring the integration of inputs from the environment. Sensory neurons, as the detectors of external stimuli, have the important role of detecting and relaying this information to the rest of the nervous system. Proper formation, connectivity, and function of dendrites and cilia in sensory neurons are essential for the detection of stimuli. In this thesis, I use the power of invertebrate genetic systems to explore the development and function of these neuronal structures.

In the first part of my thesis, I use the Drosophila melanogaster larval PNS to explore the role of three different genes in dendritic morphology and neuronal function. The dendritic arborization (DA) neurons are sensory neurons that elaborate complex and diverse dendritic morphologies beneath the epidermis. I find that Argonaute 1 (Ago1), an important part of the microRNA pathway, and Argonaute 2 (Ago2), an essential component RNAi pathway, do not have a role in dendrite patterning. However, Ago2 does regulate expression of pickpocket1 mRNA, a channel that regulates larval locomotion. Additionally, I find that mutations in the BTB-POZ domain transcription factor longitudinals lacking reduce dendrite elaboration.

In the second half of my thesis, I use Caenorhabditis elegans as a model organism to examine the role of the Bardet-Biedl Syndrome genes, required for intraflagellar transport in cilia, in metabolic homeostasis. bbs mutant worms display increased lipid accumulation, as revealed by the lipophilic dye Nile Red. Surprisingly, in a comprehensive analysis of cilia mutants, mutations in only some intraflagellar transport components alter fat content, suggesting that generally interfering with cilia formation and signaling does not affect lipid levels. A series of epistasis experiments reveal that these IFT genes participate in the bb pathway to regulate intestinal lipid accumulation. Intriguingly, the heterotrimeric kinesin-II kap-1 functions downstream of bbs. I then use candidate gene approaches and RNAi screens to seek an understanding of how bbs genes regulate fat stores. Taken together, these studies provide insight into the formation and function of sensory neuronal processes.

The main protein quality control systems, the ubiquitin-proteasome system and macroautophagy, have been implicated in a diverse range of neurodegenerative disease as well as alcoholic liver disease. Chronic ethanol use increases the load of misfolded and polyubiquitinated proteins in liver tissue and the nervous system, thereby exacerbating the effect of aging and disease. Study of the interplay of age, toxin and disease is a promising avenue for understanding each alone as well as the interplay of the three, an increasingly important topic in our aging society. This paper will discuss the evidence for ethanol's interference with protein quality control and consider the implications for neurodegenerative disease.