| Transactivating function (AF) 2-mediated AF-1 activity of estrogen receptor α is crucial to maintain male reproductive tract function. | |
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MedLine Citation:
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PMID: 23213263 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Estrogen receptor alpha (ERα) is a ligand-dependent transcription factor containing two transcriptional activation function (AF) domains. AF-1 is in the N terminus of the receptor protein, and AF-2 activity is dependent on helix 12 of the C-terminal ligand-binding domain. We recently showed that two point mutations converting leucines 543 and 544 to alanines in helix 12 (AF2ER) minimized estrogen-dependent AF-2 transcriptional activation. A characteristic feature of AF2ER is that the estrogen antagonists ICI182780 and tamoxifen (TAM) act as agonists through intact AF-1, but not through mutated AF-2. Here we report the reproductive phenotype of male AF2ER knock-in (AF2ERKI) mice and demonstrate the involvement of ERα in male fertility. The AF2ERKI male homozygotes are infertile because of seminiferous tubular dysmorphogenesis in the testis, similar to ERα KO males. Sperm counts and motility did not differ at age 6 wk in AF2ERKI and WT mice, but a significant testis defect was observed in adult AF2ERKI male mice. The expression of efferent ductal genes involved in fluid reabsorption was significantly lower in AF2ERKI males. TAM treatment for 3 wk beginning at age 21 d activated AF-2-mutated ERα (AF2ER) and restored expression of efferent ductule genes. At the same time, the TAM treatment reversed AF2ERKI male infertility compared with the vehicle-treated group. These results indicate that the ERα AF-2 mutation results in male infertility, suggesting that the AF-1 is regulated in an AF-2-dependent manner in the male reproductive tract. Activation of ERα AF-1 is capable of rescuing AF2ERKI male infertility. |
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Authors:
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Yukitomo Arao; Katherine J Hamilton; Eugenia H Goulding; Kyathanahalli S Janardhan; Edward M Eddy; Kenneth S Korach |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural Date: 2012-12-04 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 109 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-12-19 Completed Date: 2013-02-28 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 21140-5 Citation Subset: IM |
Affiliation:
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Receptor Biology Group, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Estradiol / analogs & derivatives, pharmacology Estrogen Receptor alpha / chemistry, metabolism* Fertility Homozygote Ligands Male Mice Mice, Knockout Point Mutation Protein Structure, Tertiary Reproduction Sperm Count Sperm Motility Tamoxifen / pharmacology Testis / metabolism Transcriptional Activation |
| Grant Support | |
ID/Acronym/Agency:
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Z01ES70065/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Estrogen Receptor alpha; 0/Ligands; 10540-29-1/Tamoxifen; 129453-61-8/fulvestrant; 50-28-2/Estradiol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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