Rapid signaling mechanisms of estrogens in the developing cerebellum

Abstract

The steroid hormone 17β-Estradiol regulates the normal function and development of the mammalian nervous system. Many of estradiol's effects are mediated via the nuclear hormone estrogen receptors ERα and ERβ. In addition to regulating estrogen-responsive gene expression, estradiol also acts in an immediate and cell-specific fashion to regulate various intracellular signal transduction pathways. The goal of this review is to develop a contextual framework to understand the generalized function of estrogen during development of brain regions not known to be sexually specialized. However, it is first important to build this generalized framework on the more well-developed foundation of estrogen's gonad-driven sex-specific actions. As a result, a discussion of known and proposed mechanisms of estrogen actions in reproductive and other tissues will be presented. Building upon this information, a review of our research group's recent in vitro and in vivo studies that have focused on elucidating the mechanisms of estrogen actions in neurons of the non-sexually specialized cerebellum will be presented. While the full-spectrum of estrogen action during normal cerebellar development remains unresolved, results of recent studies have revealed a pathologic role for estrogen and estrogen receptors in medulloblastoma, common pediatric brain tumors that arise from cerebellar granule cell-like precursors. The potential use of anti-estrogen signaling agents as adjuvant therapy for medulloblastoma is proposed based on those finding.

Strain-specific induction of endometrial periglandular fibrosis in mice exposed during adulthood to the endocrine disrupting chemical bisphenol A

“…These complex dose-response relationships can be a result of several separate, yet simultaneously acting, mechanisms of action [89]. Estrogens and BPA are known to act with numerous receptor mediated pathways, either through classical nuclear receptor or rapid signaling mechanisms [90, 91]. While BPA has estrogen-like activity at ERα and ERβ at nM concentrations [92], it can also bind to and inhibit the androgen and thyroid hormone receptors at μM concentrations [93–96] to cause oppositional effects at low and high dose ranges.…”

Rapid Estrogen Receptor-Mediated Mechanisms Determine the Sexually Dimorphic Sensitivity of Ventricular Myocytes to 17β-Estradiol and the Environmental Endocrine Disruptor Bisphenol A

“…The activated receptors may act as nuclear ERs to regulate estrogen-responsive gene expression and influence a wide range of physiological functions. Estradiol also directly activates intracellular signaling pathways via membrane or cytoplasmic localized ER-like receptors (12,13). Whereas the nuclear hormone receptor effects of E 2 in the heart have been well studied, the nature and mechanism of the rapid estrogen signaling in the heart and its integrated contribution to the cardiac actions of E 2 are not fully understood.…”

Hormones and Cerebellar Development

“…16.5, the different expression profiles of ERa and ERb suggest that E2 exerts its actions in a cell-type specific manner via binding to the two ERs, which play distinctive roles in cerebellar development. The possibility of rapid estrogen signaling mechanisms in the developing cerebellum has been recently discussed elsewhere (Belcher 2008).…”