PUBLICATION

Defects in exosome biogenesis are associated with sensorimotor defects in zebrafish vps4a mutants

Authors
Shipman, A., Gao, Y., Liu, D., Sun, S., Zang, J., Sun, P., Syed, Z., Bhagavathi, A., Smith, E., Erickson, T., Hill, M., Neuhauss, S., Sui, S.F., Nicolson, T.
ID
ZDB-PUB-241027-6
Date
2024
Source
The Journal of neuroscience : the official journal of the Society for Neuroscience   44(50): (Journal)
Registered Authors
Erickson, Timothy, Gao, Yan, Hill, Matthew, Neuhauss, Stephan, Nicolson, Teresa, Shipman, Anna, Smith, Eliot, Sun, Peng, Zang, Jingjing
Keywords
none
MeSH Terms
  • Mutation*
  • Larva
  • Zebrafish*
  • ATPases Associated with Diverse Cellular Activities/genetics
  • ATPases Associated with Diverse Cellular Activities/metabolism
  • Animals, Genetically Modified
  • Motor Neurons/metabolism
  • Animals
  • Endosomal Sorting Complexes Required for Transport/genetics
  • Endosomal Sorting Complexes Required for Transport/metabolism
  • Zebrafish Proteins*/genetics
  • Zebrafish Proteins*/metabolism
  • Reflex, Startle/genetics
  • Exosomes*/genetics
  • Exosomes*/metabolism
(all 15)
PubMed
39455257 Full text @ J. Neurosci.
Abstract
Mutations in human VPS4A are associated with neurodevelopmental defects, including motor delays and defective muscle tone. VPS4A encodes a AAA-ATPase required for membrane scission, but how mutations in VPS4A lead to impaired control of motor function is not known. Here we identified a mutation in zebrafish vps4a, T248I, that affects sensorimotor transformation. Biochemical analyses indicate that the T248I mutation reduces the ATPase activity of Vps4a and disassembly of ESCRT filaments, which mediate membrane scission. Consistent with the role for Vps4a in exosome biogenesis, vps4aT248I larvae have enlarged endosomal compartments in the CNS and decreased numbers of circulating exosomes in brain ventricles. Resembling the central form of hypotonia in VPS4A patients, motor neurons and muscle cells are functional in mutant zebrafish. Both somatosensory and vestibular inputs robustly evoke tail and eye movements, respectively. In contrast, optomotor responses, vestibulospinal, and acoustic startle reflexes are absent or strongly impaired in vps4aT248I larvae, indicating a greater sensitivity of these circuits to the T248I mutation. ERG recordings revealed intensity-dependent deficits in the retina, and in vivo calcium imaging of the auditory pathway identified a moderate reduction in afferent neuron activity, partially accounting for the severe motor impairments in mutant larvae. Further investigation of central pathways in vps4aT248I mutants showed that activation of descending vestibulospinal and midbrain motor command neurons by sensory cues is strongly reduced. Our results suggest that defects in sensorimotor transformation underly the profound yet selective effects on motor reflexes resulting from the loss of membrane scission mediated by Vps4a.Significance Statement Here we present a T248I mutation in vps4a, which causes sensorimotor defects in zebrafish larvae. Vps4a plays a key role in membrane scission. Spanning biochemical to systems level analyses, our study indicates that a reduction in Vps4a enzymatic activity leads to abnormalities in membrane-scission dependent processes such as endosomal protein trafficking and exosome biogenesis, resulting in pronounced deficits in sensorimotor transformation of visual, auditory, and vestibular cues. We suggest that the mechanisms underlying this type of dysfunction in zebrafish may also contribute to the condition seen in human patients with de novo mutations in the human VPS4A orthologue.
Genes / Markers
Figures
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
b692
    		Point Mutation
    st201
      		Point Mutation
      zf415TgTransgenic Insertion
        zf3262TgTransgenic Insertion
          1 - 4 of 4
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          Human Disease / Model
          No data available
          Sequence Targeting Reagents
          Target Reagent Reagent Type
          vps4aCRISPR1-vps4aCRISPR
          vps4aCRISPR2-vps4aCRISPR
          vps4aCRISPR3-vps4aCRISPR
          vps4aCRISPR4-vps4aCRISPR
          vps4bCRISPR1-vps4bCRISPR
          vps4bCRISPR2-vps4bCRISPR
          vps4bCRISPR3-vps4bCRISPR
          vps4bCRISPR4-vps4bCRISPR
          1 - 8 of 8
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          Fish
          No data available
          Antibodies
          No data available
          Orthology
          No data available
          Engineered Foreign Genes
          Marker Marker Type Name
          GAL4EFGGAL4
          GCaMPEFGGCaMP
          GFPEFGGFP
          1 - 3 of 3
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          Mapping
          No data available
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          Citation
          Shipman, A., Gao, Y., Liu, D., Sun, S., Zang, J., Sun, P., Syed, Z., Bhagavathi, A., Smith, E., Erickson, T., Hill, M., Neuhauss, S., Sui, S.F., Nicolson, T. (2024) Defects in exosome biogenesis are associated with sensorimotor defects in zebrafish vps4a mutants. The Journal of neuroscience : the official journal of the Society for Neuroscience. 44(50):.