Zebrafish Cacna1fa is required for cone photoreceptor function and synaptic ribbon formation

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Mutations in the humanCACNA1Fgene cause incomplete congenital stationary night blindness type 2 (CSNB2), a non-progressive, clinically heterogeneous retinal disorder. However, the molecular mechanisms underlying CSNB2 have not been fully explored. Here, we describe the positional cloning of a blind zebrafish mutant,wait until dark(wud), which encodes a zebrafish homolog of human CACNA1F. We identified two zebrafishcacna1fparalogs and showed that thecacna1fatranscript (the gene mutated inwud) is expressed exclusively in the photoreceptor layer. We demonstrated that Cacna1fa localizes at the photoreceptor synapse and is absent fromwudmutants. Electroretinograms revealed abnormal cone photoreceptor responses fromwudmutants, indicating a defect in synaptic transmission. Although there are no obvious morphological differences, we found thatwudmutants lacked synaptic ribbons and thatwudis essential for the development of synaptic ribbons. We found that Ribeye, the most prominent synaptic ribbon protein, was less abundant and mislocalized in adultwudmutants. In addition to cloningwud, we identifiedsynaptojanin 1(synj1) as the defective gene inslacker(slak), a blind mutant with floating synaptic ribbons. We determined that Cacna1fa was expressed inslakphotoreceptors and that Synj1 was initially expressedwudphotoreceptors, but was absent by 5 days postfertilization. Collectively, our data demonstrate that Cacna1fa is essential for cone photoreceptor function and synaptic ribbon formation and reveal a previously unknown yet critical role of L-type voltage-dependent calcium channels in the expression and/or distribution of synaptic ribbon proteins, providing a new model to study the clinical variability in human CSNB2 patients.

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