Document Detail


Transactivating function (AF) 2-mediated AF-1 activity of estrogen receptor α is crucial to maintain male reproductive tract function.
MedLine Citation:
PMID:  23213263     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Yukitomo Arao; Katherine J Hamilton; Eugenia H Goulding; Kyathanahalli S Janardhan; Edward M Eddy; Kenneth S Korach
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural     Date:  2012-12-04
Journal Detail:
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:
Created Date:  2012-12-19     Completed Date:  2013-02-28     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  21140-5     Citation Subset:  IM    
Affiliation:
Receptor Biology Group, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
Z01ES70065/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Estrogen Receptor alpha; 0/Ligands; 10540-29-1/Tamoxifen; 22X328QOC4/fulvestrant; 50-28-2/Estradiol
Comments/Corrections

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