Sex Hormones in Autism Androgens and Estrogens Differentially and Reciprocally Regulate RORA, a Novel Candidate Gene for Autism 英文参考文献.docVIP

SexHormonesinAutism:AndrogensandEstrogens DifferentiallyandReciprocallyRegulateRORA,aNovel CandidateGeneforAutism TewaritSarachana,MinyiXu,Ray-ChangWu,ValerieW.Hu* DepartmentofBiochemistryandMolecularBiology,TheGeorgeWashingtonUniversityMedicalCenter,Washington,D.C.,UnitedStatesofAmerica Abstract Autism, a pervasive neurodevelopmental disorder manifested by deficits in social behavior and interpersonal communication, and by stereotyped, repetitive behaviors, is inexplicably biased towards males by a ratio of ,4:1, with noclearunderstandingofwhetherorhowthesexhormonesmayplayaroleinautismsusceptibility.Here,weshowthat male and female hormones differentially regulate the expression of a novel autism candidate gene, retinoic acid-related orphan receptor-alpha (RORA) in a neuronal cell line, SH-SY5Y. In addition, we demonstrate that RORA transcriptionally regulates aromatase, an enzyme that converts testosterone to estrogen. We further show that aromatase protein is significantly reduced in the frontal cortex of autistic subjects relative to sex- and age-matched controls, and is strongly correlated with RORA protein levels in the brain. These results indicate that RORA has the potential to be under both negativeandpositivefeedbackregulationbymaleandfemalehormones,respectively,throughoneofitstranscriptional targets,aromatase,andfurthersuggestamechanismforintroducingsexbiasinautism. Citation:SarachanaT,XuM,WuR-C,HuVW(2011)SexHormonesinAutism:AndrogensandEstrogensDifferentiallyandReciprocallyRegulateRORA,aNovel CandidateGeneforAutism.PLoSONE6(2):e17116.doi:10.1371/journal.pone.0017116 Editor:MarkMattson,NationalInstituteonAgingIntramuralResearchProgram,UnitedStatesofAmerica ReceivedDecember1,2010;AcceptedJanuary21,2011;PublishedFebruary16,2011 Copyright: ? 2011 Sarachana et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginala