Peng Sun

All Publications

• 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 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

  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.

  View details for DOI 10.1523/JNEUROSCI.0680-24.2024

  View details for PubMedID 39455257

• Differential expression of mechanotransduction complex genes in auditory/vestibular hair cells in zebrafish. Frontiers in molecular neuroscience Smith, E. T., Sun, P., Yu, S. K., Raible, D. W., Nicolson, T. 2023; 16: 1274822

  Abstract

  Ciliated sensory cells such as photo- and olfactory receptors employ multiple types of opsins or hundreds of unique olfactory G-protein coupled receptors to respond to various wavelengths of light or odorants. With respect to hearing and balance, the mechanotransduction machinery involves fewer variants; however, emerging evidence suggests that specialization occurs at the molecular level. To address how the mechanotransduction complex varies in the inner ear, we characterized the expression of paralogous genes that encode components required for mechanotransduction in zebrafish hair cells using RNA-FISH and bioinformatic analysis. Our data indicate striking zonal differences in the expression of two components of the mechanotransduction complex which are known to physically interact, the transmembrane channel-like 1 and 2 (tmc1/2) family members and the calcium and integrin binding 2 and 3 (cib2/3) paralogues. tmc1, tmc2b, and cib3 are largely expressed in peripheral or extrastriolar hair cells, whereas tmc2a and cib2 are enriched in central or striolar hair cells. In addition, a gene implicated in deaf-blindness, ush1c, is highly enriched in a subset of extrastriolar hair cells. These results indicate that specific combinations of these components may optimize responses to mechanical stimuli in subtypes of sensory receptors within the inner ear.

  View details for DOI 10.3389/fnmol.2023.1274822

  View details for PubMedID 38035267

  View details for PubMedCentralID PMC10682102

• Transmembrane channel-like (Tmc) subunits contribute to frequency sensitivity in the zebrafish utricle. The Journal of neuroscience : the official journal of the Society for Neuroscience Sun, P., Smith, E., Nicolson, T. 2023

  Abstract

  Information about dynamic head motion is conveyed by a central 'striolar' zone of vestibular hair cells and afferent neurons in the inner ear. How vestibular hair cells are tuned to transduce dynamic stimuli at the molecular level is not well understood. Here we take advantage of the differential expression pattern of tmc1, tmc2a and tmc2b, which encode subunits of the mechanotransduction complex in zebrafish vestibular hair cells. To test the role of various combinations of Tmc subunits in transducing dynamic head movements, we measured reflexive eye movements induced by high frequency stimuli in single versus double tmc mutants. We found that tmc2a correlates with the broadest range of frequency sensitivity, whereas tmc2b mainly contributes to lower frequency responses. tmc1, which is excluded from the striolar zone, plays a minor role in sensing lower frequency stimuli. Our study suggests that the Tmc subunits impart functional differences to mechanotransduction of dynamic stimuli.Significance Statement Information about dynamic head movements is transmitted by sensory receptors, known as hair cells, in the labyrinth of the inner ear. The sensitivity of hair cells to fast or slow movements of the head differs according to cell type. Whether the mechanotransduction complex that converts mechanical stimuli into electrical signals in hair cells participates in conveying frequency information is not clear. Here we find that the transmembrane channel like 1/2 genes, which encode a central component of the complex, are differentially expressed in the utricle and contribute to frequency sensitivity in zebrafish.

  View details for DOI 10.1523/JNEUROSCI.1298-23.2023

  View details for PubMedID 37952940