Egr2Cre Mediated Conditional Ablation of Dicer Disrupts Histogenesis of Mammalian Central Auditory Nuclei 英文参考文献.docVIP

Egr2::CreMediatedConditionalAblationofDicer DisruptsHistogenesisofMammalianCentralAuditory Nuclei ElenaRosengauer1,HeinerHartwich1,AnnaMariaHartmann1,AnyaRudnicki2 ,Somisetty VenkataSatheesh1,KarenB.Avraham2,HansGerdNothwang1,3* 1DepartmentofNeurogenetics,CarlvonOssietzkyUniversityOldenburg,Oldenburg,Germany,2DepartmentofHumanMolecularGeneticsandBiochemistry,Sackler FacultyofMedicine,TelAvivUniversity,TelAviv,Israel,3CenterforNeuroscience,CarlvonOssietzkyUniversityOldenburg,Oldenburg,Germany Abstract Histogenesis of the auditory system requires extensive molecular orchestration. Recently, Dicer1, an essential gene for generation of microRNAs, and miR-96 were shown to be important for development of the peripheral auditory system. Here,weinvestigatedtheirrolefortheformationoftheauditorybrainstem.Egr2::Cre-mediatedearlyembryonicablationof Dicer1 caused severe disruption of auditory brainstem structures. In adult animals, the volume of the cochlear nucleus complex(CNC)wasreducedby73.5%.Thisdecreaseisinpartattributedtothelackofthemicroneuronalshell.Incontrast, fusiform cells, which similar to the granular cells of the microneural shell are derived from Egr2 positive cells, were still present.ThevolumereductionoftheCNCwasalreadypresentatbirth(67.2%decrease).Thesuperiorolivarycomplexwas also drastically affected in these mice. Nissl staining as well as Vglut1 and Calbindin 1 immunolabeling revealed that principal SOC nuclei such as the medial nucleus of the trapezoid body and the lateral superior olive were absent. Only cholineacetyltransferasepositiveneuronsoftheolivocochlearbundlewereobservedasadenselypackedcellgroupinthe ventrolateral area of the SOC. Mid-embryonic ablation of Dicer1 in the ventral cochlear nucleus by Atoh7::Cre-mediated recombinationresultedinnormalformationofthecochlearnucleuscomplex,indicatinganearlyembryonicrequirementof Dicer1.QuantitativeRT-PCRanalysisofmiR-96demonstratedlowexpressionintheembryonicbrainstemandup-regulation thereafter,suggesting