Disabled-2 Is Essential for Endodermal Cell Positioning and Structure Formation during Mouse Embryogenesis☆

[摘要] ThesignaltransductionadapterproteinDisabled-2(Dab2)isoneofthetwomammalianorthologsoftheDrosophilaDisabled.Thebrain-specificDisabled-1(Dab1)functionsinpositionalorganizationofbraincellsduringdevelopment.Dab2iswidelydistributedandishighlyexpressedinmanyepithelialcelltypes.Thedab2genewasinterruptedbyin-frameinsertionofβ-galactosidase(LacZ)inembryonicstemcellsandtransgenicmicewereproduced.Dab2expressionwasfirstobservedintheprimitiveendodermatE4.5,immediatelyfollowingimplantation.ThehomozygousDab2-deficientmutantisembryoniclethal(earlierthanE6.5)duetodefectivecellpositioningandstructureformationofthevisceralendoderm.InE5.5dab2(−/−)conceptus,visceralendoderm-likecellsarepresentinthedeformedprimitiveeggcylinder;however,thevisceralendodermcellsarenotorganized,thecellsoftheepiblasthavenotexpanded,andtheproamnioticcavityfailstoform.Disorganizationofthevisceralendodermallayerisevident,ascellswithpositivevisceralendodermmarkersarescatteredthroughoutthedab2(−/−)conceptus.OnlydegeneratedremainswereobservedatE6.5fordab2(−/−)embryos,andbyE7.5,thedefectiveembryoswerecompletelyreabsorbed.Inblastocystinvitroculture,initiallycellswithcharacteristicsofendoderm,trophectoderm,andinnercellmasswereobservedintheoutgrowthofthehatcheddab2(−/−)blastocysts.However,thedab2(−/−)endodermalcellsaremuchmoredispersedanddisorganizedthanthosefromwild-typeblastocysts,theinnercellmassfailstoexpand,andtheoutgrowthdegeneratesbyday7.Thus,Dab2isrequiredforvisceralendodermalcellorganizationduringearlymousedevelopment.TheabsenceofanorganizedvisceralendoderminDab2-deficientconceptusleadstothegrowthfailureoftheinnercellmass.WesuggestthatDab2functionsinasignalpathwaytoregulateendodermalcellorganizationusingendocytosisofligandsfromtheblastocoelcavityasapositioningcue.

[学科分类] 生物科学（综合）

[关键词] Disabled-2;visceral endoderm;cell positioning/organization;embryos;extraembryonic endoderm;blastocysts;differentiation;endocytosis