Meta-analysis reveals a lack of sexual dimorphism in human amygdala volume.

The amygdala plays a key role in many affective behaviors and psychiatric disorders that differ between men and women. To test whether human amygdala volume (AV) differs reliably between the sexes, we performed a systematic review and meta-analysis of AVs reported in MRI studies of age-matched healthy male and female groups. Using four search strategies, we identified 46 total studies (58 matched samples) from which we extracted effect sizes for the sex difference in AV. All data were converted to Hedges g values and pooled effect sizes were calculated using a random-effects model. Each dataset was further meta-regressed against study year and average participant age. We found that uncorrected amygdala volume is about 10% larger in males, with pooled sex difference effect sizes of g=0.581 for right amygdala (κ=28, n=2022), 0.666 for left amygdala (κ=28, n=2006), and 0.876 for bilateral amygdala (κ=16, n=1585) volumes (all p values < 0.001). However, this difference is comparable to the sex differences in intracranial volume (ICV; g=1.186, p<.001, 11.9% larger in males, κ=11) and total brain volume (TBV; g=1.278, p<0.001, 11.5% larger in males, κ=15) reported in subsets of the same studies, suggesting the sex difference in AV is a product of larger brain size in males. Among studies reporting AVs normalized for ICV or TBV, sex difference effect sizes were small and not statistically significant: g=0.171 for the right amygdala (p=0.206, κ=13, n=1560); 0.233 for the left amygdala (p=0.092, κ=12, n=1512); and 0.257 for bilateral volume (p=0.131, κ=5, n=1629). These values correspond to less than 0.1% larger corrected right AV and 2.5% larger corrected left AV in males compared to females. In summary, AV is not selectively enhanced in human males, as often claimed. Although we cannot rule out subtle male-female group differences, it is not accurate to refer to the human amygdala as "sexually dimorphic."

The human hippocampus is not sexually-dimorphic: Meta-analysis of structural MRI volumes.

Hippocampal atrophy is found in many psychiatric disorders that are more prevalent in women. Sex differences in memory and spatial skills further suggest that males and females differ in hippocampal structure and function. We conducted the first meta-analysis of male-female difference in hippocampal volume (HCV) based on published MRI studies of healthy participants of all ages, to test whether the structure is reliably sexually dimorphic. Using four search strategies, we collected 68 matched samples of males' and females' uncorrected HCVs (in 4418 total participants), and 36 samples of male and female HCVs (2183 participants) that were corrected for individual differences in total brain volume (TBV) or intracranial volume (ICV). Pooled effect sizes were calculated using a random-effects model for left, right, and bilateral uncorrected HCVs and for left and right HCVs corrected for TBV or ICV. We found that uncorrected HCV was reliably larger in males, with Hedges' g values of 0.545 for left hippocampus, 0.526 for right hippocampus, and 0.557 for bilateral hippocampus. Meta-regression revealed no effect of age on the sex difference in left, right, or bilateral HCV. In the subset of studies that reported it, both TBV (g=1.085) and ICV (g=1.272) were considerably larger in males. Accordingly, studies reporting HCVs corrected for individual differences in TBV or ICV revealed no significant sex differences in left and right HCVs (Hedges' g ranging from +0.011 to -0.206). In summary, we found that human males of all ages exhibit a larger HCV than females, but adjusting for individual differences in TBV or ICV results in no reliable sex difference. The frequent claim that women have a disproportionately larger hippocampus than men was not supported.

Two new and distinct roles for Drosophila Argonaute-2 in the nucleus: alternative pre-mRNA splicing and transcriptional repression.

Transcription and pre-mRNA alternative splicing are highly regulated processes that play major roles in modulating eukaryotic gene expression. It is increasingly apparent that other pathways of RNA metabolism, including small RNA biogenesis, can regulate these processes. However, a direct link between alternative pre-mRNA splicing and small RNA pathways has remained elusive. Here we show that the small RNA pathway protein Argonaute-2 (Ago-2) regulates alternative pre-mRNA splicing patterns of specific transcripts in the Drosophila nucleus using genome-wide methods in conjunction with RNAi in cell culture and Ago-2 deletion or catalytic site mutations in Drosophila adults. Moreover, we show that nuclear Argonaute-2 binds to specific chromatin sites near gene promoters and negatively regulates the transcription of the Ago-2-associated target genes. These transcriptional target genes are also bound by Polycomb group (PcG) transcriptional repressor proteins and change during development, implying that Ago-2 may regulate Drosophila development. Importantly, both of these activities were independent of the catalytic activity of Ago-2, suggesting new roles for Ago-2 in the nucleus. Finally, we determined the nuclear RNA-binding profile of Ago-2, found it bound to several splicing target transcripts, and identified a G-rich RNA-binding site for Ago-2 that was enriched in these transcripts. These results suggest two new nuclear roles for Ago-2: one in pre-mRNA splicing and one in transcriptional repression.

The Drosophila splicing factor PSI is phosphorylated by casein kinase II and tousled-like kinase.

Alternative splicing of pre-mRNA is a highly regulated process that allows cells to change their genetic informational output. These changes are mediated by protein factors that directly bind specific pre-mRNA sequences. Although much is known about how these splicing factors regulate pre-mRNA splicing events, comparatively little is known about the regulation of the splicing factors themselves. Here, we show that the Drosophila splicing factor P element Somatic Inhibitor (PSI) is phosphorylated at at least two different sites by at minimum two different kinases, casein kinase II (CK II) and tousled-like kinase (tlk). These phosphorylation events may be important for regulating protein-protein interactions involving PSI. Additionally, we show that PSI interacts with several proteins in Drosophila S2 tissue culture cells, the majority of which are splicing factors.