A mutation in the silver gene leads to defects in melanosome biogenesis and alterations in the visual system in the zebrafish mutant fading vision

摘要

Forwardgeneticscreenshavebeeninstrumentalindefiningmolecularcomponentsofvisualfunction.Thezebrafishmutantemfadingvision/em(emfdv/em)hasbeenidentifiedinsuchascreenduetodefectsinvisionaccompaniedbyhypopigmentationintheretinalpigmentepithelium(RPE)andbodymelanocytes.TheRPEformstheoutermostlayeroftheretina,anditsfunctionisessentialforvision.Inemfdv/emmutantlarvae,theoutersegmentsofphotoreceptorsarestronglyreducedinlengthorabsentduetodefectsinRPEcells.UltrastructuralanalysisofRPEcellsrevealsdramaticcellularchangessuchasanabsenceofmicrovilliandvesicularinclusions.Theretinoidprofileisalteredasjudgedbybiochemicalanalysis,arguingforapartialblockinvisualpigmentregeneration.Surprisingly,homozygousemfdv/emvisionmutantssurvivetoadulthoodandshow,despiteapersistenceofthehypopigmentation,apartialrecoveryofretinalmorphology.Bypositionalcloningandsubsequentmorpholinoknock-down,weidentifiedamutationintheemsilver/emgeneasthemoleculardefectunderlyingtheemfdv/emphenotype.TheSilverproteinisrequiredforintralumenalfibrilformationinmelanosomesbyamylogeniccleavage.Ourdatarevealanunexpectedlinkbetweenmelanosomebiogenesisandthevisualsystem,undetectableincellculture./p/div