TY - JOUR
T1 - Novel mechanisms of estrogen action in the brain
T2 - New players in an old story
AU - Toran-Allerand, C. Dominique
AU - Singh, Meharvan
AU - Sétáló, György
N1 - Funding Information:
Many thanks are due to Drs. Wayne D. L. Bentham, Xiaoping Guan, Elisabetta Mauri, Rajesh Miranda, and Farida Sohrabji for their contributions over the years to the work described in this paper. We thank Ms. Cynthia Leung and Mr. Matthew F. Warren for their expert technical assistance and Dr. Lloyd A. Greene (Columbia University) for constructive discussions. The research was supported in part by grants to C.D.T.-A. from NIH (NIA), NIMH, NSF, the American Health Assistance Foundation (AHAF), the Bader Foundation, and the Alzheimer’s Association/ Burks B. Lapham grant and an ADAMHA Research Scientist Award to C.D.T.-A.
PY - 1999/4
Y1 - 1999/4
N2 - Estrogen elicits a selective enhancement of the growth and differentiation of axons and dendrites (neurites) in the developing brain. Widespread colocalization of estrogen and neurotrophin receptors (trk) within estrogen and neurotrophin targets, including neurons of the cerebral cortex, sensory ganglia, and PC12 cells, has been shown to result in differential and reciprocal transcriptional regulation of these receptors by their ligands. In addition, estrogen and neurotrophin receptor coexpression leads to convergence or cross-coupling of their signaling pathways, particularly at the level of the mitogen-activated protein (MAP) kinase cascade. 17β- Estradiol elicits rapid (within 5-15 min) and sustained (at least 2 h) tyrosine phosphorylation and activation of the MAP kinases, extracellular- signal regulated kinase (ERK)1, and ERK2, which is successfully inhibited by the MAP kinase/ERK kinase 1 inhibitor PD98059, but not by the estrogen receptor (ER) antagonist ICI 182,780 and also does not appear to result from estradiol-induced activation of trk. Furthermore, the ability of estradiol to phosphorylate ERK persists even in ER-α knockout mice, implicating other estrogen receptors such as ER-β in these actions of estradiol. The existence of an estrogen receptor-containing, multimeric complex consisting of hsp90, src, and B-Raf also suggests a direct link between the estrogen receptor and the MAP kinase signaling cascade. Collectively, these novel findings, coupled with our growing understanding of additional signaling substrates utilized by estrogen, provide alternative mechanisms for estrogen action in the developing brain which could explain not only some of the very rapid effects of estrogen, but also the ability of estrogen and neurotrophins to regulate the same broad array of cytoskeletal and growth-associated genes involved in neurite growth and differentiation. This review expands the usually restrictive view of estrogen action in the brain beyond the confines of sexual differentiation and reproductive neuroendocrine function. It considers the much broader question of estrogen as a neural growth factor with important influences on the development, survival, plasticity, regeneration, and aging of the mammalian brain and supports the view that the estrogen receptor is not only a ligand-induced transcriptional enhancer but also a mediator of rapid, nongenomic events.
AB - Estrogen elicits a selective enhancement of the growth and differentiation of axons and dendrites (neurites) in the developing brain. Widespread colocalization of estrogen and neurotrophin receptors (trk) within estrogen and neurotrophin targets, including neurons of the cerebral cortex, sensory ganglia, and PC12 cells, has been shown to result in differential and reciprocal transcriptional regulation of these receptors by their ligands. In addition, estrogen and neurotrophin receptor coexpression leads to convergence or cross-coupling of their signaling pathways, particularly at the level of the mitogen-activated protein (MAP) kinase cascade. 17β- Estradiol elicits rapid (within 5-15 min) and sustained (at least 2 h) tyrosine phosphorylation and activation of the MAP kinases, extracellular- signal regulated kinase (ERK)1, and ERK2, which is successfully inhibited by the MAP kinase/ERK kinase 1 inhibitor PD98059, but not by the estrogen receptor (ER) antagonist ICI 182,780 and also does not appear to result from estradiol-induced activation of trk. Furthermore, the ability of estradiol to phosphorylate ERK persists even in ER-α knockout mice, implicating other estrogen receptors such as ER-β in these actions of estradiol. The existence of an estrogen receptor-containing, multimeric complex consisting of hsp90, src, and B-Raf also suggests a direct link between the estrogen receptor and the MAP kinase signaling cascade. Collectively, these novel findings, coupled with our growing understanding of additional signaling substrates utilized by estrogen, provide alternative mechanisms for estrogen action in the developing brain which could explain not only some of the very rapid effects of estrogen, but also the ability of estrogen and neurotrophins to regulate the same broad array of cytoskeletal and growth-associated genes involved in neurite growth and differentiation. This review expands the usually restrictive view of estrogen action in the brain beyond the confines of sexual differentiation and reproductive neuroendocrine function. It considers the much broader question of estrogen as a neural growth factor with important influences on the development, survival, plasticity, regeneration, and aging of the mammalian brain and supports the view that the estrogen receptor is not only a ligand-induced transcriptional enhancer but also a mediator of rapid, nongenomic events.
KW - Brain
KW - Cross-coupling
KW - Estradiol
KW - Estrogen receptor
KW - Neurotrophin receptors, signal transduction
KW - Neurotrophins
UR - http://www.scopus.com/inward/record.url?scp=0032907868&partnerID=8YFLogxK
U2 - 10.1006/frne.1999.0177
DO - 10.1006/frne.1999.0177
M3 - Article
C2 - 10328986
AN - SCOPUS:0032907868
SN - 0091-3022
VL - 20
SP - 97
EP - 121
JO - Frontiers in Neuroendocrinology
JF - Frontiers in Neuroendocrinology
IS - 2
ER -