Alternative splicing of Wilms tumor suppressor 1 (Wt1) exon 4 results in protein isoforms with different functions

摘要

TheWilmstumorsuppressorgeneemWt1/emencodesazincfingertranscriptionfactorthatisessentialfordevelopmentofmultipleorgansincludingkidneys,gonads,spleenandheart.InmammalsemWt1/emcomprises10exonswithtwocharacteristicsplicingevents:inclusionorskippingofexon5andalternativeusageoftwosplicedonorsitesbetweenexons9and10.Mostfishincludingzebrafishandmedakapossesstwoemwt1/emparalogs,emwt1a/emandemwt1b/em,bothlackingexon5.Herewehavecharacterizedemwt1/eminguppy,platyfishandtheshort-livedAfricankillifishemNothobranchiusfurzeri/em.Allfishexceptzebrafishshowalternativesplicingofexon4ofemwt1a/embutnotofemwt1b/emwiththeemwt1a/em(emminus;exon4/em)isoformbeingthepredominantsplicevariant.Withregardtofunction,Wt1a(+exon4)showedlessdimerizationbutstimulatedtranscriptionmoreeffectivelythantheWt1a(emminus;/emexon4)isoform.Aspecificknockdownofemwt1a/emexon4inzebrafishwasassociatedwithanomaliesinkidneydevelopmentdemonstratingaphysiologicalfunctionforWt1aexon4.Interestingly,alternativesplicingofexon4seemstobeanearlyevolutionaryeventasitisobservedinthesingleemwt1/emgeneofthesturgeon,aspeciesthathasnotgonethroughteleost-specificgenomeduplication./p/div