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A New Zebrafish Model for CACNA2D4-Dysfunction
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DOI：10.1167/iovs.19-26759.png)
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PURPOSE. Mutations in CACNA2D4, encoding the alpha(2)delta(4) subunit of retinal voltage-gated calcium channels (Ca-v), cause a rare type of retinal dysfunction in human, mainly affecting cone vision. Here, we investigate the role of CACNA2D4 in targeting of Ca-v, its influence on cone-mediated signal transmission, and the cellular and subcellular changes upon loss of alpha(2)delta(4) by exploiting the advantages of the cone-dominant zebrafish as model system. METHODS. We identified two zebrafish CACNA2D4 paralogs (cacna2d4a and cacna2d4b), analyzed their expression by RNA in situ hybridization and introduced truncating frameshift mutations through CRISPR/Cas9-mediated mutagenesis. We analyzed retinal function and morphology of the single and double mutant lines by electroretinography, immunohistochemistry, light- and electron microscopy. RESULTS. Knockout of cacna2d4b reduces the expression of Cacna1fa, the pore-forming subunit of retinal Ca(v)1.4, whereas loss of cacna2d4a did not. Only knockout of both paralogs impaired cone-mediated ERG b-wave amplitude. The number of floating'' ribbons is increased in double-KO, while retinal morphology and expression of postsynaptic mGluR6b remain largely unaffected. Both Cacna1fa and Ribeyeb show ectopic punctate expression in cacna2d4b-KO and double-KO photoreceptors. CONCLUSIONS. We find that increasing the expression of Ca-v at the synaptic membrane is an evolutionarily conserved function of Cacna2d4b. Yet, since both paralogs participate in cone synaptic transmission, we propose partial subfunctionalization in zebrafish. Similar to human patients, our double KO zebrafish model shows mild cone dysfunction, which was not associated with signs of retinal degeneration. Therefore, cacna2d4-KO zebrafish is a suitable model to study the pathophysiological mechanisms underlying CACNA2D4 dysfunction in human.
Keyword:
calcium channel
cone photoreceptor
zebrafish
disease model
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论文数:
1.7W
被引数:
5.5W
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引用论文
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