Oxytocin sets the stage for childbirth by initiating uterine contractions, lactation and maternal bonding behaviours. Mice lacking secreted oxcytocin (
Oxt
−/−
,
Cd38
−/−
) or its receptor (
Oxtr
−/−
) fail to nurture. Normal maternal behaviour is restored by peripheral oxcytocin replacement in
Oxt
−/−
and
Cd38
−/−
, but not
Oxtr
−/−
mice, implying that circulating oxcytocin crosses the blood-brain barrier. Exogenous oxcytocin also has behavioural effects in humans. However, circulating polypeptides are typically excluded from the brain. We show that oxcytocin is transported into the brain by receptor for advanced glycation end-products (RAGE) on brain capillary endothelial cells. The increases in oxcytocin in the brain which follow exogenous administration are lost in
Ager
−/−
male mice lacking RAGE, and behaviours characteristic to abnormalities in oxcytocin signalling are recapitulated in
Ager
−/−
mice, including deficits in maternal bonding and hyperactivity. Our findings show that RAGE-mediated transport is critical to the behavioural actions of oxcytocin associated with parenting and social bonding.
In mammals, follicular atresia can be partially triggered by granulosa cell apoptosis. However, very little is known about the functions of miRNAs in granulosa cell apoptosis. We previously reported that hsa-mir-23a (miR-23a) and hsa-mir-27a (miR-27a) were highly expressed in the plasma of patients with premature ovarian failure, but the action of these two miRNAs in follicular development was unclear. In this study, we explored the roles of miR-23a and miR-27a in the granulosa cells of women undergoing in vitro fertilization/embryo transfer. Using Hoechst staining, we found that miR-23a and miR-27a promoted apoptosis in human granulosa cells. In addition, the Western blotting results suggested that the miR-23a/miR-27a-mediated apoptosis occurred via the FasL-Fas pathway. Based on the results of a luciferase-reporter assay and quantitative RT-PCR and Western blotting analyses, we found that SMAD5 is a target gene of both miR-23a and miR-27a. Furthermore, knocking down SMAD5 expression increased the rate of apoptosis, as well as the levels of Fas, FasL, cleaved caspase-8, and cleaved caspase-3 protein. Taken together, these data suggest that miR-23a and miR-27a target SMAD5 and regulate apoptosis in human granulosa cells via the FasL-Fas pathway. These findings provide an improved understanding of the mechanisms underlying granulosa cell apoptosis, which could potentially be used for future clinical applications.
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