Structural and functional characteristics of oestrogen receptor splice variants: Implications for the ageing brain

Oestrogen receptor (ER) is a multifunctional nuclear receptor that mediates the actions of oestrogenic compounds. Despite its well defined role in mediating the actions of oestrogens, a substantial body of evidence demonstrates that ER has a broad range of physiological functions independent of those normally attributed to oestrogen signalling. These functions can partly be achieved by the activity of several alternatively spliced isoforms that have been identified for ER. This short review describes structural differences between the ER splice variants that are known to be translated into proteins. Moreover, we discuss how these alternative structures contribute to functional differences in the context of both healthy and pathological conditions. Our review also describes the principal factors that regulate alternative RNA splicing. The alternatively spliced isoforms of ER are differentially expressed according to brain region, age and hormonal milieu, emphasising the likelihood that there are precise cell-specific mechanisms regulating ER alternative splicing. However, despite these correlative data, the molecular factors regulating alternative ER splicing in the brain remain unknown. We also review the basic mechanisms that regulate alternative RNA splicing and use that framework to make logical predictions about ER alternative splicing in the brain.