The vestibulospinal nucleus is a locus of balance development

Hamling, Kyla R.; Harmon, Katherine; Kimura, Yukiko; Higashijima, Shin-ichi; Schoppik, David

doi:10.1101/2023.12.06.570482

Cited by 3 publications

(2 citation statements)

References 70 publications

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“…Hindbrain VS neurons, which directly innervate trunk motor neurons, have decreased neuronal activity in mutants. Recently it was shown that ablation of VS neurons leads to modest defects in posture in zebrafish larvae [98], suggesting that other vestibular circuits contribute to postural control. The reduced activation of the vestibulospinal pathway in vps4a T248I mutants may therefore only partially account for the inability to maintain an upright posture.…”

Section: Discussionmentioning

confidence: 99%

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Defects in exosome biogenesis are associated with sensorimotor defects in zebrafishvps4amutants

Shipman,

Gao,

Liu

et al. 2024

Preprint

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Mutations in humanVPS4Aare associated with neurodevelopmental defects, including motor delays and defective muscle tone.VPS4Aencodes a AAA-ATPase that is required for membrane scission, but how mutations inVPS4Alead to impaired control of motor function is not known. Here we identified a mutation in zebrafishvps4a, T248I, that affects sensorimotor transformation. In biochemical experiments we show that the T248I mutation reduces the ATPase activity of Vps4a and disassembly of its substrate, ESCRT filaments, which mediate membrane scission. Consistent with the established role for Vps4a in the endocytic pathway and exosome biogenesis,vps4aT248Imutants have enlarged endosomal compartments in the CNS and decreased numbers of circulating exosomes. Resembling the central form of hypotonia in humanVPS4Apatients, motor neurons and muscle cells are unaffected in mutant zebrafish as they react robustly to touch. Unlike somatosensory function, optomotor responses, vestibulospinal (VS), and acoustic startle reflexes are severely impaired invps4aT248Imutants, indicating a greater sensitivity of these circuits to the T248I mutation. ERG recordings indicate that visual ability is largely reduced in the mutants, however,in vivoimaging of tone-evoked responses in the inner ear and ascending auditory pathway show comparable activity. Further investigation of central pathways invps4aT248Imutants revealed that sensory cues failed to fully activate neurons in the VS and medial longitudinal fasciculus (MLF) nuclei that directly innervate motor neurons. Our results suggest that a defect in sensorimotor transformation underlies the profound yet selective effects on motor reflexes resulting from the loss of membrane scission mediated by Vps4a.

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Section: Discussionmentioning

confidence: 99%

Section: Sensory and Motor Deficitsmentioning

confidence: 99%

Defects in exosome biogenesis are associated with sensorimotor defects in zebrafishvps4amutants

Shipman,

Gao,

Liu

et al. 2024

Preprint

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A brainstem circuit for gravity-guided vertical navigation

Zhu,

Gelnaw,

Auer

et al. 2024

Preprint

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The sensation of gravity anchors our perception of the environment and is crucial for navigation. However, the neural circuits that transform gravity into commands for navigation are undefined. We first determined that larval zebrafish (Danio rerio) navigate vertically by maintaining a consistent heading across a series of upward climb or downward dive bouts. Gravity-blind mutant fish swim with more variable heading and excessive veering, leading to inefficient vertical navigation. After targeted photoablation of ascending vestibular neurons and spinal projecting midbrain neurons, but not vestibulospinal neurons, vertical navigation was impaired. These data define a sensorimotor circuit that uses evolutionarily-conserved brainstem architecture to transform gravitational signals into persistent heading for vertical navigation. The work lays a foundation to understand how vestibular inputs allow animals to move efficiently through their environment.

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Defects in Exosome Biogenesis Are Associated with Sensorimotor Defects in Zebrafish vps4a Mutants

Shipman,

Gao,

Liu

et al. 2024

J. Neurosci.

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Mutations in humanVPS4Aare associated with neurodevelopmental defects, including motor delays and defective muscle tone.VPS4Aencodes a AAA-ATPase required for membrane scission, but how mutations inVPS4Alead to impaired control of motor function is not known. Here we identified a mutation in zebrafishvps4a, 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,vps4aT248Ilarvae have enlarged endosomal compartments in the CNS and decreased numbers of circulating exosomes in brain ventricles. Resembling the central form of hypotonia inVPS4Apatients, 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 invps4aT248Ilarvae, 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 invps4aT248Imutants 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 StatementHere we present a T248I mutation invps4a, 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 withde novomutations in the humanVPS4Aorthologue.

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The vestibulospinal nucleus is a locus of balance development

Cited by 3 publications

References 70 publications

Defects in exosome biogenesis are associated with sensorimotor defects in zebrafishvps4amutants

Defects in exosome biogenesis are associated with sensorimotor defects in zebrafishvps4amutants

A brainstem circuit for gravity-guided vertical navigation

Defects in Exosome Biogenesis Are Associated with Sensorimotor Defects in Zebrafish vps4a Mutants

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