BACKGROUND Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by significant impairment in reciprocal social interactions and communication coupled with stereotyped, repetitive behaviors and restricted interests. Although genomic and functional studies are beginning to reveal some of the genetic complexity and underlying pathobiology of ASD, the consistently reported male bias of ASD remains an enigma. We have recently proposed that retinoic acid-related orphan receptor alpha (RORA), which is reduced in the brain and lymphoblastoid cell lines of multiple cohorts of individuals with ASD and oppositely regulated by male and female hormones, might contribute to the sex bias in autism by differentially regulating target genes, including CYP19A1 (aromatase), in a sex-dependent manner that can also lead to elevated testosterone levels, a proposed risk factor for autism. METHODS In this study, we examine sex differences in RORA and aromatase protein levels in cortical tissues of unaffected and affected males and females by re-analyzing pre-existing confocal immunofluorescence data from our laboratory. We further investigated the expression of RORA and its correlation with several of its validated transcriptional targets in the orbital frontal cortex and cerebellum as a function of development using RNAseq data from the BrainSpan Atlas of the Developing Human Brain. In a pilot study, we also analyzed the expression of Rora and the same transcriptional targets in the cortex and cerebellum of adult wild-type male and female C57BL/6 mice. RESULTS Our findings suggest that Rora/RORA and several of its transcriptional targets may exhibit sexually dimorphic expression in certain regions of the brain of both mice and humans. Interestingly, the correlation coefficients between Rora expression and that of its targets are much higher in the cortex of male mice relative to that of female mice. A strong positive correlation between the levels of RORA and aromatase proteins is also seen in the cortex of control human males and females as well as ASD males, but not ASD females. CONCLUSIONS Based on these studies, we suggest that disruption of Rora/RORA expression may have a greater impact on males, since sex differences in the correlation of RORA and target gene expression indicate that RORA-deficient males may experience greater dysregulation of genes relevant to ASD in certain brain regions during development.

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研究RORA及其转录靶标在大脑中的性别差异，这可能是自闭症中性别偏见的潜在原因。

背景技术自闭症谱系障碍（ASD）是一种神经发育疾病，其特征在于相互的社交互动和交流受到严重损害，并伴有刻板的，重复的行为和受限制的兴趣。尽管基因组和功能研究开始揭示ASD的某些遗传复杂性和潜在的病理生物学，但一直以来报道的ASD男性偏见仍然是一个谜。我们最近提出，视黄酸相关的孤儿受体α（RORA）可能会导致自闭症中的性别偏见通过差异调节靶基因，包括CYP19A1（芳香酶），以性别依赖的方式，也可能导致睾丸激素水平升高，这是自闭症的拟议危险因素。方法在本研究中，我们通过重新分析来自实验室的共聚焦免疫荧光数据，研究了未受影响和受影响的男性和女性皮质组织中RORA和芳香酶蛋白水平的性别差异。我们使用来自人类大脑BrainSpan Atlas的RNAseq数据，进一步研究了RORA的表达及其与眶额皮质和小脑中其若干经过验证的转录靶标的相关性，作为发育的函数。在一项先导研究中，我们还分析了成年野生型雄性和雌性C57BL / 6小鼠皮质和小脑中Rora和相同转录靶标的表达。结果我们的发现表明，Rora / RORA及其一些转录靶标在小鼠和人类大脑的某些区域可能表现出性二态表达。有趣的是，与雌性小鼠相比，雄性小鼠皮层中Rora表达与其靶标之间的相关系数要高得多。在对照人的雄性和雌性以及ASD雄性的皮层中，也观察到了RORA和芳香酶蛋白水平之间的强正相关，而ASD雌性则没有。结论基于这些研究，我们建议中断Rora / RORA表达可能会对男性产生更大的影响，