Structural and functional characteristics of estrogen receptor beta (ERβ) splice variants: implications for the aging brain

Abstract

Estrogen receptor beta (ERβ) is a multifunctional nuclear receptor that mediates the actions of estrogenic compounds. Despite its well defined role in mediating the actions of estrogens, a substantial body of evidence demonstrates that ERβ has broad range of physiological functions that are independent of those normally attributed to estrogen signaling. These functions can, in part, be achieved by the activity of several alternatively spliced isoforms that have been identified for ERβ. This short review will describe structural differences between the ERβ 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. This review also describes the principal factors that regulate alternative RNA splicing. The alternatively spliced isoforms of ERβ are differentially expressed according to brain region, age, and hormonal milieu underscoring the likelihood that there are precise cell-specific mechanisms that regulate ERβ alternative splicing. However, despite these correlative data, the molecular factors regulating alternative ERβ splicing in the brain remain unknown. Here, we review the basic mechanisms that regulate alternative RNA splicing and use that framework to make logical predictions about ERβ alternative splicing in the brain.

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