UC San Diego

Neuroscience mutagenesis facility (Nmf) 9 is the name of a mouse mutant discovered as part of the Jackson Laboratory NMF N-ethyl-N-nitrosourea (ENU) mutagenesis program in 2002. The nmf9 mouse mutants were observed to show tremor and signs of vestibular dysfunction, though there were no obvious signs of deafness despite the shared developmental pathways of the vestibular and the auditory system. At the time of the observation, the nmf9 mutation had not been mapped, and the identity of the gene that is mutated as well as the gene's potential functions were all unknown. Preliminary data in our laboratory identified nmf9 as a single point mutation at a splice site, leading to an exon -skipping frame-shift in a novel, low-expressing transcript. The research presented in this dissertation demonstrates that the Nmf9 transcript is important to both vestibular development in embryos as well as functions in distinct neurocircuits in the adult brain. Furthermore, Nmf9 encodes a protein that is conserved throughout Metazoa, and shows some conservation in its functions in the Central Nervous System (CNS) and in mechanosensory structures. Lastly, the work presented here shows the first link between vestibular dysfunction and ADP- Ribosylation Factor (ARF) 5. Though various class I and class III ARFs have been linked to vestibular development via knockdown (KD) of either the ARF itself or other members of its interaction network, this is the first time that a class II ARF has been shown to play a role in this system