Identification of sexually dimorphic genes in the neonatal mouse cortex and hippocampus

Armoskus, Chris; Moreira, Debbie; Bollinger, Kayla; Jimenez, Oliva; Taniguchi, Saori; Tsai, Houng-Wei

doi:10.1016/j.brainres.2014.03.017

Cited by 70 publications

(67 citation statements)

References 108 publications

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“…The current results confirm female-biased expression of Xist , Eif2s3x , Kdm6a , and Mid1 , consistent with our previous study [30]. In addition, they demonstrate that their expression is not dependent on prenatal TP levels, indicating that in the neonatal mouse cortex/ hippocampus, these four X-linked genes are mainly regulated by X-chromosomal gene dosage, rather than sex steroids (Figure 3).…”

Section: Discussionsupporting

confidence: 92%

“…Using gene expression microarrays with reverse transcription quantitative polymerase chain reaction, we have recently identified a group of sex-biased genes expressed in the neonatal mouse cortex/ hippocampus [30]. Based on the organizational effect of T on brain sexual differentiation, we hypothesized that some of these sexually dimorphic genes might be regulated by perinatal T, leading to the development of distinct neural functions and behaviors between the sexes.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Prenatal Testosterone Exposure on Sexually Dimorphic Gene Expression in the Neonatal Mouse Cortex and Hippocampus

Armoskus

Mota

Moreira

et al. 2013

J Steroids Horm Sci

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Objective Using gene expression microarrays and reverse transcription with quantitative polymerase chain reaction (RT-qPCR), we have recently identified several novel genes that are differentially expressed in the neonatal male versus female mouse cortex/hippocampus (Armoskus et al.). Since perinatal testosterone (T) secreted by the developing testes masculinizes cortical and hippocampal structures and the behaviors regulated by these brain regions, we hypothesized that sexually dimorphic expression of specific selected genes in these areas might be regulated by T during early development. Methods To test our hypothesis, we treated timed pregnant female mice daily with vehicle or testosterone propionate (TP) starting on embryonic day 16 until the day of birth. The cortex/hippocampus was collected from vehicle- and TP-treated, male and female neonatal pups. Total RNA was extracted from these brain tissues, followed by RT-qPCR to measure relative mRNA levels of seven sex chromosome genes and three autosomal genes that have previously showed sex differences. Results The effect of prenatal TP was confirmed as it stimulated Dhcr24 expression in the neonatal mouse cortex/hippocampus and increased the anogenital distance in females. We found a significant effect of sex, but not TP, on expression of three Y-linked (Ddx3y, Eif2s3y, and Kdm5d), four X-linked (Eif2s3x, Kdm6a, Mid1, and Xist), and one autosomal (Klk8) genes in the neonatal mouse cortex/hippocampus. Conclusion Although most of the selected genes are not directly regulated by prenatal T, their sexually dimorphic expression might play an important role in the control of sexually differentiated cognitive and social behaviors as well as in the etiology of sex-biased neurological disorders and mental illnesses.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Effects of Prenatal Testosterone Exposure on Sexually Dimorphic Gene Expression in the Neonatal Mouse Cortex and Hippocampus

Armoskus

Mota

Moreira

et al. 2013

J Steroids Horm Sci

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“…The subtle magnitudes of the sex differences revealed in our study are very much in line with previous exploratory studies of sexually dimorphic gene expression [27, 33, 58–60]. For example, in a microarray study by Yang et al [27] 613 of 4508 brain expressed genes differed by >onefold between the sexes, and 37 of those 613 genes displayed a fold difference of >1.2.…”

Section: Discussionsupporting

confidence: 90%

Proteomic analyses of limbic regions in neonatal male, female and androgen receptor knockout mice

et al. 2017

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BackgroundIt is well-established that organizational effects of sex steroids during early development are fundamental for sex-typical displays of, for example, mating and aggressive behaviors in rodents and other species. Male and female brains are known to differ with respect to neuronal morphology in particular regions of the brain, including the number and size of neurons, and the density and length of dendrites in nuclei of hypothalamus and amygdala. The aim of the present study was to use global proteomics to identify proteins differentially expressed in hypothalamus/amygdala during early development (postnatal day 8) of male, female and conditional androgen receptor knockout (ARNesDel) male mice, lacking androgen receptors specifically in the brain. Furthermore, verification of selected sexually dimorphic proteins was performed using targeted proteomics.ResultsOur proteomic approach, iTRAQ, allowed us to investigate expression differences in the 2998 most abundantly expressed proteins in our dissected tissues. Approximately 170 proteins differed between the sexes, and 38 proteins between ARNesDel and control males (p < 0.05). In line with previous explorative studies of sexually dimorphic gene expression we mainly detected subtle protein expression differences (fold changes <1.3). The protein MARCKS (myristoylated alanine rich C kinase substrate), having the largest fold change of the proteins selected from the iTRAQ analyses and of known importance for synaptic transmission and dendritic branching, was confirmed by targeted proteomics as differentially expressed between the sexes.ConclusionsOverall, our results provide solid evidence that a large number of proteins show sex differences in their brain expression and could potentially be involved in brain sexual differentiation. Furthermore, our finding of a sexually dimorphic expression of MARCKS in the brain during development warrants further investigation on the involvement in sexual differentiation of this protein.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-016-0332-1) contains supplementary material, which is available to authorized users.

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“…As an internal control, we indeed found that Kdm5d and Xist were the two most differentially expressed genes between XX and XY eNSCs at baseline. Given their known sexually dimorphic expression patters21 further supports the validity of our data set (Supplemental Table 1). For additional confidence, we selected 12 of our differentially expressed genes to validate by a secondary approach of qPCR, which showed similar expression differences that were identified within our RNA-seq dataset (Supplemental Fig.…”

Section: Resultssupporting

confidence: 76%

“…Unlike other studies that have focused on sex differences in the brain caused by genetic makeup6212829, our approach used a very specific cell type as opposed to gross brain tissue, as the latter may lack the sensitivity to observe nuances in gene expression, which may be masked by heterogeneous cell populations. This limitation has been observed when looking at DNA methylation in the brain, as it was found that global profiles are striking different between individual cells and that of heterogeneous cell populations within whole brain tissue30.…”

Section: Discussionmentioning

confidence: 99%

Sex-Specific Effects of Testosterone on the Sexually Dimorphic Transcriptome and Epigenome of Embryonic Neural Stem/Progenitor Cells

Vilain

Roach

Lipson

et al. 2016

Sci Rep

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The mechanisms by which sex differences in the mammalian brain arise are poorly understood, but are influenced by a combination of underlying genetic differences and gonadal hormone exposure. Using a mouse embryonic neural stem cell (eNSC) model to understand early events contributing to sexually dimorphic brain development, we identified novel interactions between chromosomal sex and hormonal exposure that are instrumental to early brain sex differences. RNA-sequencing identified 103 transcripts that were differentially expressed between XX and XY eNSCs at baseline (FDR = 0.10). Treatment with testosterone-propionate (TP) reveals sex-specific gene expression changes, causing 2854 and 792 transcripts to become differentially expressed on XX and XY genetic backgrounds respectively. Within the TP responsive transcripts, there was enrichment for genes which function as epigenetic regulators that affect both histone modifications and DNA methylation patterning. We observed that TP caused a global decrease in 5-methylcytosine abundance in both sexes, a transmissible effect that was maintained in cellular progeny. Additionally, we determined that TP was associated with residue-specific alterations in acetylation of histone tails. These findings highlight an unknown component of androgen action on cells within the developmental CNS, and contribute to a novel mechanism of action by which early hormonal organization is initiated and maintained.

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Identification of sexually dimorphic genes in the neonatal mouse cortex and hippocampus

Cited by 70 publications

References 108 publications

Effects of Prenatal Testosterone Exposure on Sexually Dimorphic Gene Expression in the Neonatal Mouse Cortex and Hippocampus

Effects of Prenatal Testosterone Exposure on Sexually Dimorphic Gene Expression in the Neonatal Mouse Cortex and Hippocampus

Proteomic analyses of limbic regions in neonatal male, female and androgen receptor knockout mice

Sex-Specific Effects of Testosterone on the Sexually Dimorphic Transcriptome and Epigenome of Embryonic Neural Stem/Progenitor Cells

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