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Endocrinology Vol. 143, No. 5 1643-1650
Copyright © 2002 by The Endocrine Society

NEUROENDOCRINOLOGY

Estrogen-Binding Sites and Their Functional Capacity in Estrogen Receptor Double Knockout Mouse Brain

Paul J. Shughrue, G. Roger Askew, Tammy L. Dellovade and Istvan Merchenthaler

Women’s Health Research Institute, Wyeth-Ayerst Research (P.J.S., T.L.D., I.M.), Radnor, Pennsylvania 19087; and Molecular Genetics, Wyeth/Genetic Institute (G.R.A.), Andover, Massachusetts 01810

Address all correspondence and requests for reprints to: Dr. Paul J. Shughrue, Department of Neuroscience, Merck Research Laboratories, WP26A-3000, Sumneytown Pike and Broad Street, West Point, Pennsylvania 19486. E-mail: . paul_shughrue{at}merck.com

Early studies found estrogen-binding sites in the ER knockout (ER{alpha}KO) mouse brain, suggesting a splice variant of ER{alpha} or another ER. The discovery of ERß suggested that binding was due to ERß, although questions about an ER{gamma} remained. To test this hypothesis, ERßKO mice were generated and crossed with ER{alpha}KO mice, and ER{alpha}/ßKO animals were used for in vivo binding studies with [125I]estrogen. The results revealed nuclear binding sites in the ER{alpha}/ßKO hypothalamus and amygdala. As the binding resembled the distribution of ER{alpha}, we evaluated the presence of ER{alpha} splicing variants. A nonphysiological splice variant of ER{alpha} was identified in ER{alpha}/ßKO brain and uterus, but was absent in wild-type mice. ER{alpha} immunoreactivity was also detected in regions of ER{alpha}/ßKO brain where residual binding was seen. To ascertain the functionality of the variant, the regulation of PR was assessed in brain. The results revealed that E2 significantly increased PR expression, an indication that the variant can regulate gene transcription. These data demonstrate the presence and functionality of an ER{alpha} variant in ER{alpha}/ßKO brain and suggest that the residual binding and regulation of PR in ER{alpha}/ßKO brain can be accounted for by the variant.




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