Sex Difference in Mecp2 Expression During a Critical Period of Rat Brain Development

Kurian, Joseph R.; Forbes-Lorman, Robin M.; Auger, Anthony P.

doi:10.4161/epi.2.3.4841

Cited by 88 publications

(74 citation statements)

References 27 publications

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“…Females expressed higher levels of this X-chromosome gene associated with the neurodevelopmental disorder, Rett Syndrome, than did males. Others have reported a similar sex difference in Mecp2 expression in the postnatal day one rat amygdala (77), which indirectly supports our result by suggesting that the sex difference is organized by early estradiol exposure. The same group also showed that sexually dimorphic Mecp2 expression in the amygdala is required for the development of sexually dimorphic behaviors in later life (78).…”

Section: Discussionsupporting

confidence: 91%

Calbindin Knockout Alters Sex-Specific Regulation of Behavior and Gene Expression in Amygdala and Prefrontal Cortex

et al. 2016

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Calbindin-D(28K) (Calb1), a high-affinity calcium buffer/sensor, shows abundant expression in neurons and has been associated with a number of neurobehavioral diseases, many of which are sexually dimorphic in incidence. Behavioral and physiological end points are affected by experimental manipulations of calbindin levels, including disruption of spatial learning, hippocampal long-term potentiation, and circadian rhythms. In this study, we investigated novel aspects of calbindin function on social behavior, anxiety-like behavior, and fear conditioning in adult mice of both sexes by comparing wild-type to littermate Calb1 KO mice. Because Calb1 mRNA and protein are sexually dimorphic in some areas of the brain, we hypothesized that sex differences in behavioral responses of these behaviors would be eliminated or revealed in Calb1 KO mice. We also examined gene expression in the amygdala and prefrontal cortex, two areas of the brain intimately connected with limbic system control of the behaviors tested, in response to sex and genotype. Our results demonstrate that fear memory and social behavior are altered in male knockout mice, and Calb1 KO mice of both sexes show less anxiety. Moreover, gene expression studies of the amygdala and prefrontal cortex revealed several significant genotype and sex effects in genes related to brain-derived neurotrophic factor signaling, hormone receptors, histone deacetylases, and γ-aminobutyric acid signaling. Our findings are the first to directly link calbindin with affective and social behaviors in rodents; moreover, the results suggest that sex differences in calbindin protein influence behavior.

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Section: Discussionsupporting

confidence: 91%

Calbindin Knockout Alters Sex-Specific Regulation of Behavior and Gene Expression in Amygdala and Prefrontal Cortex

et al. 2016

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“…In this light, mutations in regulatory regions may be tolerable to the brain of the developing male but induce phenotypic variations. Studies in rat brain have shown significantly less Mecp2 mRNA and protein expression in the amygdala of male rat brain during the steroidsensitive period of brain development (35). Ultimately, there is ample evidence suggesting that regulation of MECP2 is different between genders, consistent with our observations of the differential influence of MECP2 variations on brain structure in males and females.…”

Section: Discussionsupporting

confidence: 88%

A common MECP2 haplotype associates with reduced cortical surface area in humans in two independent populations

Joyner

Roddey

Bloss

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

111

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The gene MECP2 is a well-known determinant of brain structure. Mutations in the MECP2 protein cause microencephalopathy and are associated with several neurodevelopmental disorders that affect both brain morphology and cognition. Although mutations in MECP2 result in severe neurological phenotypes, the effect of common variation in this genetic region is unknown. We find that common sequence variations in a region in and around MECP2 show association with structural brain size measures in 2 independent cohorts, a discovery sample from the Thematic Organized Psychosis research group, and a replication sample from the Alzheimer's Disease Neuroimaging Initiative. The most statistically significant replicated association (P < 0.025 in both cohorts) involved the minor allele of SNP rs2239464 with reduced cortical surface area, and the finding was specific to male gender in both populations. Variations in the MECP2 region were associated with cortical surface area but not cortical thickness. Secondary analysis showed that this allele was also associated with reduced surface area in specific cortical regions (cuneus, fusiform gyrus, pars triangularis) in both populations.MRI ͉ neuroscience ͉ imaging genetics

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“…Although the first studies on specific epigenetic mechanisms in brain sexual differentiation appeared less than 10 years ago [7][8][9][10], circumstantial evidence that epigenetics plays a role was available much earlier. For example, most known sex differences in the brain depend on gonadal steroid hormones, acting during a critical developmental window [11].…”

Section: Sexual Differentiation and Epigeneticsmentioning

confidence: 99%

Epigenetic mechanisms in sexual differentiation of the brain and behaviour

Forger¹

2016

Phil. Trans. R. Soc. B

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One contribution of 16 to a theme issue 'Multifaceted origins of sex differences in the brain'.Subject Areas: behaviour, developmental biology, genetics, neuroscience Keywords:DNA methylation, histone, medial preoptic area, bed nucleus of the stria terminalis, sex difference Author for correspondence: Nancy G. Forger e-mail: nforger@gsu.edu Epigenetic mechanisms in sexual differentiation of the brain and behaviour Nancy G. Forger Neuroscience Institute, Georgia State University, Atlanta, GA 30307, USA Circumstantial evidence alone argues that the establishment and maintenance of sex differences in the brain depend on epigenetic modifications of chromatin structure. More direct evidence has recently been obtained from two types of studies: those manipulating a particular epigenetic mechanism, and those examining the genome-wide distribution of specific epigenetic marks. The manipulation of histone acetylation or DNA methylation disrupts the development of several neural sex differences in rodents. Taken together, however, the evidence suggests there is unlikely to be a simple formula for masculine or feminine development of the brain and behaviour; instead, underlying epigenetic mechanisms may vary by brain region or even by dependent variable within a region. Whole-genome studies related to sex differences in the brain have only very recently been reported, but suggest that males and females may use different combinations of epigenetic modifications to control gene expression, even in cases where gene expression does not differ between the sexes. Finally, recent findings are discussed that are likely to direct future studies on the role of epigenetic mechanisms in sexual differentiation of the brain and behaviour.

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Sex Difference in Mecp2 Expression During a Critical Period of Rat Brain Development

Cited by 88 publications

References 27 publications

Calbindin Knockout Alters Sex-Specific Regulation of Behavior and Gene Expression in Amygdala and Prefrontal Cortex

Calbindin Knockout Alters Sex-Specific Regulation of Behavior and Gene Expression in Amygdala and Prefrontal Cortex

A common MECP2 haplotype associates with reduced cortical surface area in humans in two independent populations

Epigenetic mechanisms in sexual differentiation of the brain and behaviour

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