The temporal requirement for vitamin A in the developing eye: Mechanism of action in optic fissure closure and new roles for the vitamin in regulating cell proliferation and adhesion in the embryonic retina

摘要

MammalianeyedevelopmentrequiresvitaminA(retinol,ROL).TheroleofvitaminAatspecifictimesduringeyedevelopmentwasstudiedinratfetusesmadevitaminAdeficient(VAD)afterembryonicday(E)10.5(lateVAD).TheopticfissuredoesnotcloseinlateVADembryos,andseverefoldingandcollapseoftheretinaisobservedatE18.5.emPitx2/em,agenerequiredfornormalopticfissureclosure,isdramaticallydownregulatedintheperiocularmesenchymeinlateVADembryos,anddissolutionofthebasallaminadoesnotoccurattheopticfissuremargin.TheadditionofROLtolateVADembryosbyE12.5restoresemPitx2/emexpression,supportsdissolutionofthebasallamina,andpreventscoloboma,whereassupplementationatE13.5doesnot.Surprisingly,ROLgivenaslateasE13.5completelypreventsfoldingoftheretinadespitethepresenceofanopenfetalfissure,showingthatcolobomaandretinalfoldingrepresentdistinctVAD-dependentdefects.RetinalfoldingduetoVADisprecededbyanoverallreductioninthepercentageofcyclinD1positivecellsinthedevelopingretina,(initiallyresultinginretinalthinning),aswellasadramaticreductioninthecelladhesion-relatedmolecules,N-cadherinandβ-catenin.Reductionofretinalcellnumbercombinedwithalossofthenormalcellndash;celladhesionproteinsmaycontributetothecollapseandfoldingoftheretinathatoccursinlateVADfetuses./p/div