The nonsense-mediated decay pathway maintains synapse architecture and synaptic vesicle cycle efficacy.
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 the efficacy of synaptic function.
Long
A Ashleigh
AA
Department of Biological Sciences, Vanderbilt Brain Institute, Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37235-1634, USA.
Mahapatra
Cecon T
CT
Woodruff
Elvin A
EA
Rohrbough
Jeff
J
Leung
Hung-Tat
HT
Shino
Shikoh
S
An
Lingling
L
Doerge
Rebecca W
RW
Metzstein
Mark M
MM
Pak
William L
WL
Broadie
Kendal
K
D000818:Animals; D004330:Drosophila / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005816:Genetic Complementation Test; D005820:Genetic Testing; D055537:Light Signal Transduction / Q000235:genetics; D009024:Morphogenesis / Q000235:genetics; D009469:Neuromuscular Junction / Q000502:physiology; D017956:Photoreceptor Cells, Invertebrate / Q000378:metabolism* / Q000473:pathology; D017729:Presynaptic Terminals / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000254:growth & development / Q000473:pathology; D017384:Sequence Deletion / Q000235:genetics; D009435:Synaptic Transmission / Q000235:genetics; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D029721:Drosophila Proteins; D017346:Protein Serine-Threonine Kinases; C510482:nonC protein, Drosophila
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