Estrogen Receptor Null Mice - Endocrine Reviews

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June, 1999 ESTROGEN RECEPTOR NULL MICE 405 TABLE 4. Summary of reported phenotypes in the �ERKO and �ERKO mice ERKO model Description of phenotype Ref. Lethality of mutation ER� No 46, 116 ER� Fertility No 47 �ERKO Both sexes are infertile 46 �ERKO General Female is subfertile (reduced litter size); male is fertile 47 �ERKO Exhibit normal expression of the ER� gene 93, 121, 352 Female reproductive tract �ERKO Tract undergoes normal pre- and neonatal development but is insensitive to estradiol, DES, and hydroxy 46, 123, 153 tamoxifen during adulthood Presence of non-ER� or -ER� receptor-mediated estrogenic pathway for 4-OH-estradiol and methoxychlor 173, 174 Loss of mitogenic actions of EGF 170 Responsive to mitogenic actions of androgens 154 Responsive to progesterone and able to undergo artificially induced decidualization 183 Ovaries undergo normal pre- and neonatal development, but are anovulatory during adulthood, exhibit multiple hemorrhagic cysts, and no corpora lutea 46, 142 30–40% incidence of ovarian tumors by 18 months of age Herein �ERKO Tract undergoes normal pre- and neonatal development and appears sensitive to ovarian estrogen cycling 47 during adulthood Ovaries undergo normal pre- and neonatal development, but do not exhibit normal frequency of spontaneous ovulations during adulthood, exhibit a severely attenuated response to superovulation treatment with reduced numbers of oocytes and multiple trapped preovulatory follicles Mammary gland �ERKO Undergoes normal prenatal development but is insensitive to estrogen-induced development during puberty and adulthood 269 Responsive to exogenous progesterone and prolactin In preparation Susceptible to proto-oncogene (Wnt-1) induced ductal hyperplasia and lobuloalveolar adenocarcinoma but tumors exhibit a delayed growth rate compared to those in wild-type 297 �ERKO Undergoes normal prenatal and pubertal development, virgin gland is grossly indistinguishable from that of 47 age-matched wild-type Undergoes normal differentiation and lactation during pregnancy and motherhood Male reproductive tract 47 �ERKO Tract undergoes normal pre- and neonatal development 315, 316 Age-related phenotype of attenuated fluid resorption in efferent ducts leads to dilation of Rete testis, 315, 327 atrophy of the seminiferous epithelium, and decreasing sperm counts Disrupted sperm function illustrated by an inability to fertilize 315 Age-related decreases in testis weight Herein Age-related increases in seminal vesicle weight Herein �ERKO Undergoes normal pre- and neonatal development with no apparent defects in spermatogenesis that impede 47 fertility Neuroendocrine system: females �ERKO Anterior pituitary possesses all of the expected cell types but exhibits elevated transcripts for the gonadotropin subunits (�-gonadotropin subunit, LH-�, FSH-�) 282 Elevated serum levels of estradiol, testosterone, and LH, but normal serum levels of progesterone and FSH 123, 252 Normal lactotroph differentiation and number in the anterior pituitary, but exhibits significant deficits in transcription of the PRL gene and serum PRL levels 282, Herein Medial preoptic region of the hypothalamus exhibits elevated levels of PR transcripts which reduce with 400, 423 ovariectomy and return with estradiol treatment Rapid actions of estradiol on hippocampal neurons are preserved 364 �ERKO Normal serum levels of estradiol Herein Neuroendocrine system: males �ERKO Anterior pituitary possesses all the expected cell types but exhibit elevated LH-� transcripts 282, 317 Elevated serum levels of estradiol, testosterone, and LH, but normal serum levels of progesterone and FSH 317, Herein Behavior: females �ERKO Exhibit a lack of estradiol and progesterone-induced sexual behavior, increased aggression, and infanticide 417, 418, 419 �ERKO Exhibit no defects in sexual behavior that impede fertility 47 Behavior: males �ERKO Exhibit normal mounting and attraction toward wild-type females but a complete lack of intromission and 318, 427, 428 ejaculation; display reduced aggression �ERKO Exhibit no defects in sexual behavior that impede fertility 47 Cardiovascular �ERKO Exhibit reduced estradiol-induced angiogenesis and reduced basal levels of vascular nitric oxide 467 Exhibit wild-type response to estradiol in the carotid artery injury model 464 Exhibit increased expression of L-type Ca 2� channels 472 Exhibit reduced response to estrogen-induced increases in serum apolipoprotein E 460 Other �ERKO Both sexes exhibit growth arrest of longitudinal bones 447, 448 Impaired glucose tolerance 490 No apparent defect on B lymphopoiesis 507 47
406 COUSE AND KORACH Vol. 20, No. 3 fore, the �ERKO mice have played a significant role in confirming many of the roles thought to be fulfilled by estrogen, whereas the �ERKO mice have and will continue to provide primary insight into the functions of the ER�. The generation of both models, as well as a forthcoming description of the ��ERKO, will prove invaluable in elucidating the precise roles fulfilled by each ER, as well as any possible cooperative roles the two receptors might play within the same tissue or even within the same cell. Acknowledgments The authors are grateful to several individuals for their dedication, effort, and insight that has made the work described above possible: first and foremost, our original collaborators in the generation of the ERKO mice, Dr. Oliver Smithies for his efforts leading to the generation of both ERKO models; Dr. Dennis Lubahn for the �ERKO; and Drs. John Krege, Jeff Hodges, and Jan-Åke Gustafsson and laboratory for the �ERKO. The authors are exceptionally indebted to Sylvia Curtis, Todd Washburn, Dr. Jonathan Lindzey, Dr. Wayne Bocchinfuso, Mariana Yates, Linwood Koonce, James Clarke, Page Myers, Dr. Motohiko Taki, and Dr. Sean Kimbro for their efforts and dedication. We would also like to thank our several collaborators, Drs. Ralph Cooper, Richard DiAugustine, E. Mitch Eddy, Thomas Golding, Paul Kincaide, Diane Klotz, Michael Mendolsohn, Robert Moss, Jeffrey Moyer, Sonoko Ogawa, Donald Pfaff, Gabor Rubanyi, David Schomberg, Allen Silverstone, and Harold Varmus. We would also like to acknowledge Drs. Paul Shughrue and Istvan Merchenthaler for the contribution of Fig. 8. References 1. Jensen EV, DeSombre ER 1973 Estrogen-receptor interaction. Science 182:126–134 2. Jensen EV, Jacobson HI 1962 Basic guides to the mechanism of estrogen action. Recent Prog Horm Res 18:387–414 3. Toft D, Gorski J 1966 A receptor molecule for estrogens: isolation from the rat uterus and preliminary characterization. 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