The small GTPases RhoA and Rac1 regulate cerebellar development by controlling cell morphogenesis, migration and foliation

摘要

ThesmallGTPasesRhoAandRac1arekeycytoskeletalregulatorsthatfunctioninamutuallyantagonisticmannertocontrolthemigrationandmorphogenesisofabroadrangeofcelltypes.However,theirroleinshapingthecerebellum,auniquebrainstructurecomposedofanelaboratesetoffoliaseparatedbyfissuresofdifferentlengths,remainslargelyunexplored.HereweshowthatdysregulationofbothRhoAandRac1signalingresultsinabnormalcerebellarontogenesis.AblationofRhoAfromneuroprogenitorcellsdrasticallyaltersthetimingandplacementoffissureformation,themigrationandpositioningofgranuleandPurkinjecells,thealignmentofBergmannglia,andtheintegrityofthebasementmembrane,primarilyintheanteriorlobules.Furthermore,intheabsenceofRhoA,granulecellprecursorslocatedatthebaseoffissuresfailtoundergocellshapechangesrequiredforfissureinitiation.ManyoftheseabnormalitiescanberecapitulatedbydeletingRhoAspecificallyfromgranulecellprecursorsbutnotpostnatalglia,indicatingthatRhoAfunctionsingranulecellprecursorstocontrolcerebellarmorphogenesis.Notably,micewithelevatedRac1activityduetolossoftheRac1inhibitorsBcrandAbrshowsimilaranteriorcerebellardeficits,includingectopicneuronsanddefectsinfissureformation,Bergmanngliaorganizationandbasementmembraneintegrity.Together,ourresultssuggestthatRhoAandRac1playindispensablerolesinpatterningcerebellarmorphology./p/div