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Title page for ETD etd-07262010-130933


Type of Document Dissertation
Author Long, Amanda Ashleigh
URN etd-07262010-130933
Title Characterization of novel genes regulating the synaptic vesicle cycle in drosophila
Degree PhD
Department Biological Sciences
Advisory Committee
Advisor Name Title
Todd Graham Committee Chair
David Miller Committee Member
Donna Webb Committee Member
Kendal Broadie Committee Member
Keywords
  • photoreceptor
  • synapse
  • neurotransmission
  • synaptic vesicle cycle
  • Drosophila
  • mRNA regulation
  • Smg1
  • NMD pathway
Date of Defense 2010-07-12
Availability unrestricted
Abstract
A systematic Drosophila forward genetic screen for photoreceptor synaptic transmission mutants identified no-on-and-no-off transient C (nonC) based on loss of retinal synaptic responses to light stimulation. The cloned gene encodes phosphatidylinositol 3-kinase-like kinase (PIKK) Smg1, a regulatory kinase of the nonsense-mediated decay (NMD) pathway. The Smg proteins act in an mRNA quality control surveillance mechanism to selectively degrade transcripts containing premature stop codons, thereby preventing the translation of truncated proteins with dominant negative or deleterious gain of function activities. At the neuromuscular junction (NMJ) synapse, an extended allelic series of Smg1 mutants show impaired structural architecture, with decreased terminal arbor size, branching and synaptic bouton number. Functionally, loss of Smg1 results in a ~50% reduction in basal neurotransmission strength, as well as progressive transmission fatigue and greatly impaired synaptic vesicle recycling during high-frequency stimulation. Mutation of other NMD pathways genes (Upf2 and Smg6) similarly impairs neurotransmission and synaptic vesicle cycling. These findings suggest that the NMD pathway acts to regulate proper mRNA translation to safeguard synapse morphology and maintain synaptic functional efficacy.
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