Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice

Developmental Biology

Aaron L Nelson¹  David H Rowitch¹  Sibel A Algon¹  Ondrea Graves¹  Liliana C Goumnerova¹  Scott L Pomeroy¹  John Y.H Kim¹  Rosalind A Segal¹  Lisa Marie Sturla¹ 

DOI  :  10.1016/S0012-1606(03)00434-2

学科分类：生物科学（综合）

来源: Academic Press

【 摘 要 】

MedulloblastomaisacerebellartumorthatcanarisethroughaberrantactivationofSonichedgehog(Shh)signaling,whichnormallyregulatescerebellargranulecellproliferation.MutationsoftheShhreceptorPATCHED(PTCH)areassociatedwithmedulloblastomas,whichhavenotbeenfoundtohavelossofPTCHheterozygosity.Weaddresswhetherpatched(Ptc)heterozygosityfundamentallyaltersgranulecelldifferentiationandcontributestotumorigenesisbyincreasingproliferationand/ordecreasingapoptosisinPtc+/minus;mice.OurdatashowthatpostnatalPtc+/minus;mousegranulecellprecursorgrowthisnotgloballyaltered.However,manyolderPtc+/minus;micedisplayabnormalcerebellarregionscontainingpersistentlyproliferatinggranulecellprecursors.SincefewerPtc+/minus;miceformmedulloblastomas,thesegranulecellrestsrepresentadevelopmentallydisrupted,butuncommittedstageoftumorigenesis.AlthoughPtc+/minus;mousemedulloblastomasexpressneurodevelopmentalgenes,theydivergefromgranulecelldifferentiationintheirdiscordantcoexpressionofpostmitoticmarkersdespitetheirongoinggrowth.Likehumanmedulloblastomas,mousetumorswithreducedlevelsoftheneurotrophin-3receptor,trkC/Ntrk3,displaydecreasedapoptosisinvivo,illustratingtheroleofTrkCinregulatingtumorcellsurvival.TheseresultsindicatethatPtcheterozygositycontributestotumorigenesisbypredisposingasubsetofgranulecellprecursorstotheformationofproliferativerestsandsubsequentdysregulationofdevelopmentalgeneexpression.

【 授权许可】

Unknown   

【 预 览 】

附件列表

Files	Size	Format	View
RO201912090729623ZK.pdf	2210KB	PDF