title: The kinesin-3, unc-104 regulates dendrite morphogenesis and synaptic development in Drosophila.
abstract: Kinesin-based transport is important for synaptogenesis, neuroplasticity, and maintaining synaptic function. In an anatomical screen of neurodevelopmental mutants, we identified the exchange of a conserved residue (R561H) in the forkhead-associated domain of the kinesin-3 family member Unc-104/KIF1A as the genetic cause for defects in synaptic terminal- and dendrite morphogenesis. Previous structure-based analysis suggested that the corresponding residue in KIF1A might be involved in stabilizing the activated state of kinesin-3 dimers. Herein we provide the first in vivo evidence for the functional importance of R561. The R561H allele (unc-104(bris)) is not embryonic lethal, which allowed us to investigate consequences of disturbed Unc-104 function on postembryonic synapse development and larval behavior. We demonstrate that Unc-104 regulates the reliable apposition of active zones and postsynaptic densities, possibly by controlling site-specific delivery of its cargo. Next, we identified a role for Unc-104 in restraining neuromuscular junction growth and coordinating dendrite branch morphogenesis, suggesting that Unc-104 is also involved in dendritic transport. Mutations in KIF1A/unc-104 have been associated with hereditary spastic paraplegia and hereditary sensory and autonomic neuropathy type 2. However, we did not observe synapse retraction or dystonic posterior paralysis. Overall, our study demonstrates the specificity of defects caused by selective impairments of distinct molecular motors and highlights the critical importance of Unc-104 for the maturation of neuronal structures during embryonic development, larval synaptic terminal outgrowth, and dendrite morphogenesis.
authors.affiliation: Junior Research Group Synaptic Plasticity, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Jeannine V
authors.initials: JV
authors.lastname: Kern
authors.forename: Yao V
authors.initials: YV
authors.lastname: Zhang
authors.forename: Stella
authors.initials: S
authors.lastname: Kramer
authors.forename: Jay E
authors.initials: JE
authors.lastname: Brenman
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Rasse
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D048708:Cell Growth Processes; D003712:Dendrites / Q000648:ultrastructure*; D004330:Drosophila / Q000166:cytology / Q000235:genetics* / Q000254:growth & development / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008124:Locomotion; D008969:Molecular Sequence Data; D009024:Morphogenesis; D020125:Mutation, Missense; D009469:Neuromuscular Junction / Q000166:cytology / Q000254:growth & development*
chemical_list: D029721:Drosophila Proteins; C587248:Unc-104 protein, Drosophila; D016547:Kinesins
keywords: FHA domain; hereditary spastic paraplegia; kinesin-3; synapse