Document Type

Journal Article

Publication Date

2015

Journal

Molecular Autism

Volume

Volume 6

Inclusive Pages

Article number 7

DOI

10.1186/2040-2392-6-7

Abstract

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 RORAand 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.

Comments

Reproduced with permission of BioMed Central. Molecular Autism.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Peer Reviewed

1

Open Access

1

Samples and data from confocal immunofluorescence analyses.pdf (58 kB)
Samples and data from confocal immunofluorescence analyses

RNAseq data from BrainSpan.xlsx (16 kB)
RNAseq data from BrainSpan

Primers for mouse expression analyses.pdf (55 kB)
Primers for mouse expression analyses

Correlation plots for RORA-target gene expression in the OFC.pdf (539 kB)
Correlation plots for RORA-target gene expression in the OFC

Correlation plots for RORA-target gene expression in the cerebellum.pdf (559 kB)
Correlation plots for RORA-target gene expression in the cerebellum

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