Gonadectomy differentially regulates steroid receptor coactivator-1 and synaptic proteins in the hippocampus of adult female and male C57BL/6 mice.

Hippocampus is one of the most important structures that mediates learning and memory, cognition, and mental behaviors and profoundly regulated by sex hormones in a sex-specific manner, but the mechanism of underlying sex differences regulation is still unclear. We have previously reported that in the male and female mice, steroid receptor coactivator-1 (SRC-1) and some key synaptic proteins share similar developmental profile in the hippocampus, but how circulating sex hormones affect hippocampal SRC-1 as well as these synaptic proteins remain unclear. In this study, we examined how gonad sex hormones regulate hippocampal SRC-1, synaptophysin, PSD-95, and AMPA receptor subtype GluR1 by using immunohistochemistry and Western blot. The results showed that in the female mice, ovariectomy affected hippocampal SRC-1 and GluR1 were only detected at 2 weeks post operation, then it recovered to sham level; synaptophysin was unaffected at any timepoint examined; significant decrease of PSD-95 was only detected at 4 weeks post operation. However, in the male hippocampus, SRC-1 and PSD-95 were decreased from one week and lasted to 4 weeks after orchidectomy, GluR1 decreased from 2 weeks after orchidectomy, but synaptophysin remained unchanged as in the females. Correlation analysis showed the profiles of SRC-1 were positively correlated with GluR1 of the females, PSD-95 and GluR1 of the males, respectively. The above results suggested a distinct regulatory mode between female and male gonad hormones in the regulation of hippocampal SRC-1 and synaptic proteins, which may be one of the mechanisms contributing to the dimorphism of hippocampus during development and ageing.

Localization and sex-difference of steroid receptor coactivator-1 immunoreactivities in the brain of adult female and male mice.

Females and males are different in brain and behaviors. These differences are mediated by steroids and their nuclear receptors which require coactivators to regulate the transcription of target genes. Studies have shown that these coactivators are critical for modulating steroid hormone action in the brain. Steroid receptor coactivator-1 has been implied in the regulation of reproduction, stress, motor learning, and limited studies have reported the sex-specific difference of SRC-1 mRNA or protein expression in specific brain regions, but the expression and differences of SRC-1 immunoreactivities in adult female and male brain remain unclear. In this study we reported that in both sexes, high levels of SRC-1 immunoreactivities were detected in olfactory bulb, cerebral cortex, hippocampus, Purkinje cells, some limited diencephalon and brainstem nuclei. The immunopositive materials were predominantly detected in cell nucleus, but in some regions they were also detected in the processes or fiber-like structures. In most of the brain regions studied, males possessed significantly higher levels of SRC-1 immunoreactivities than that of females. Higher levels of SRC-1 were detected in some nuclei related to learning and memory, motor regulation and reproduction indicated its potential roles in neurodegeneration and sex-dependent behavior and structure; the region- and sex-specific localization of SRC-1 immunoreactivities in agreement with that of some steroid receptors, indicating this coactivator play important roles in these hormone-reactive regions and cell groups related to reproduction, learning and memory, integration of motor and sense.

Retinoic acid signalling induces the differentiation of mouse fetal liver-derived hepatic progenitor cells.

BACKGROUND: Hepatic progenitor cells (HPCs) can be isolated from fetal liver and extrahepatic tissues. Retinoic acid (RA) signalling plays an important role in development, although the role of RA signalling in liver-specific progenitors is poorly understood. AIMS: We sought to determine the role of RA in regulating hepatic differentiation. METHODS: RNA was isolated from liver tissues of various developmental stages. Liver marker expression was assessed by reverse transcriptase-polymerase chain reaction and immunofluorescence staining. Reversibly immortalized HPCs derived from mouse embryonic day 14.5 (E14.5) liver (aka, HP14.5) were established. Albumin promoter-driven reporter (Alb-GLuc) was used to monitor hepatic differentiation. Glycogen synthesis was assayed as a marker for terminal hepatic differentiation. RESULTS: Retinoic acid receptor (RAR)-alpha, retinoid X receptor (RXR)-alpha and RXR-gamma expressed in E12.5 to postnatal day 28 liver samples. Expression of RAR-beta and RXR-beta was low perinatally, whereas RAR-gamma was undetectable in prenatal tissues and increased postnatally. Retinal dehydrogenase 1 and 2 (Raldh1 and Raldh2) were expressed in all tissues, while Raldh3 was weakly expressed in prenatal samples but was readily detected postnatally. Nuclear receptor corepressors were highly expressed in all tissues, while expression of nuclear co-activators decreased in perinatal tissues and increased after birth. HP14.5 cells expressed high levels of early liver stem cell markers. Expression of RA signalling components and coregulators was readily detected in HP14.5. RA was shown to induce Alb-GLuc activity and late hepatocyte markers. RA was further shown to induce glycogen synthesis in HP14.5 cells, an important function of mature hepatocytes. CONCLUSIONS: Our results strongly suggest that RA signalling may play an important role in regulating hepatic differentiation.