ArticleProceedings of the National Academy of Sciences of the United States of America2012
Transactivating function (AF) 2-mediated AF-1 activity of estrogen receptor α is crucial to maintain male reproductive tract function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 37 citations in OpenAlex.
- A comparison of the expression patterns and diagnostic capability of the ncRNAs NEAT1 and miR-34a in non-obstructive azoospermia and severe oligospermia.Human genomics · 2025Article
- Role for Nongenomic Estrogen Signaling in Male Fertility.Endocrinology · 2024Article
- The physiological role of estrogen receptor functional domains.Essays in biochemistry · 2021Review
- Estrogen and estrogen receptors in kidney diseases.Renal failure · 2021Review
- The genomic regulatory elements for estrogen receptor alpha transactivation-function-1 regulated genes.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Peri- and Postpubertal Estrogen Exposures of Female Mice Optimize Uterine Responses Later in Life.Endocrinology · 2020Article
- Transactivation Function-1-Mediated Partial Agonist Activity of Selective Estrogen Receptor Modulator Requires Homo-Dimerization of the Estrogen Receptor α Ligand Binding Domain.International journal of molecular sciences · 2019Review
- N-terminal transactivation function, AF-1, of estrogen receptor alpha controls obesity through enhancement of energy expenditure.Molecular metabolism · 2018Article
- Estrogen Receptors: New Directions in the New Millennium.Endocrine reviews · 2018Review
- Estrogen in the male: a historical perspective.Biology of reproduction · 2018Review
- Estrogens in Male Physiology.Physiological reviews · 2017Review
- Estrogen Hormone Biology.Current topics in developmental biology · 2017Review
- The role of epigenetics in idiopathic male infertility.Journal of assisted reproduction and genetics · 2016Review
- Oestrogen action and male fertility: experimental and clinical findings.Cellular and molecular life sciences : CMLS · 2015Review
- Transactivation Function-2 of Estrogen Receptor α Contains Transactivation Function-1-regulating Element.The Journal of biological chemistry · 2015Article
- Estrogen hormone physiology: reproductive findings from estrogen receptor mutant mice.Reproductive biology · 2014Review
- Minireview: dynamic structures of nuclear hormone receptors: new promises and challenges.Molecular endocrinology (Baltimore, Md.) · 2014Review
- The Transactivating Function 2 (AF-2) of Estrogen Receptor (ER) α is Indispensable for ERα-mediated Physiological Responses and AF-1 Activity.Open journal of endocrine and metabolic diseases · 2013Article
- Estrogen receptor α L543A,L544A mutation changes antagonists to agonists, correlating with the ligand binding domain dimerization associated with DNA binding activity.The Journal of biological chemistry · 2013Article
- Disruption of estrogen receptor signaling and similar pathways in the efferent ductules and initial segment of the epididymis.SpermatogenesisReview
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
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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