Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene.

Lubahn, Dennis B.; Moyer, Jeffrey S.; Golding, Thomas S.; Couse, John F.; Korach, Kenneth S.; Smithies, Oliver

doi:10.1073/pnas.90.23.11162

Cited by 1,690 publications

(1,106 citation statements)

References 34 publications

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“…Many studies have underlined the importance of estrogens in male fertility [5,[32][33][34], as demonstrated by the expression of ERs and aromatase in the testis and by the fact that mice lacking either ERa [5] or aromatase [6] show altered spermatogenesis and infertility. However, evidence for a direct action of E 2 on the seminiferous epithelium is still missing, and remarkably genes that are regulated by E 2 through classical ERE sequences remain unknown in the testis.…”

Section: Discussionmentioning

confidence: 99%

The faah gene is the first direct target of estrogen in the testis: role of histone demethylase LSD1

Grimaldi

Pucci

Siena

et al. 2012

Cell. Mol. Life Sci.

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Estrogen (E 2 ) regulates spermatogenesis, yet its direct target genes have not been identified in the testis. Here, we cloned the proximal 5 0 flanking region of the mouse fatty acid amide hydrolase (faah) gene upstream of the luciferase reporter gene, and demonstrated its promoter activity and E 2 inducibility in primary mouse Sertoli cells. Specific mutations in the E 2 response elements (ERE) of the faah gene showed that two proximal ERE sequences (ERE2/3) are essential for E 2 -induced transcription, and chromatin immunoprecipitation experiments showed that E 2 induced estrogen receptor b binding at ERE2/3 sites in the faah promoter in vivo. Moreover, the histone demethylase LSD1 was found to be associated with ERE2/3 sites and to play a role in mediating E 2 induction of FAAH expression. E 2 induced epigenetic modifications at the faah proximal promoter compatible with transcriptional activation by remarkably decreasing methylation of both DNA at CpG site and histone H3 at lysine 9. Finally, FAAH silencing abolished E 2 protection against apoptosis induced by the FAAH substrate anandamide. Taken together, our results identify FAAH as the first direct target of E 2 .

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Section: Discussionmentioning

confidence: 99%

The faah gene is the first direct target of estrogen in the testis: role of histone demethylase LSD1

Grimaldi

Pucci

Siena

et al. 2012

Cell. Mol. Life Sci.

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“…These results were con®rmed and strengthened by experiments in which the MMTV-Wnt-1 transgene was crossed into the ERa knockout (ERKO) mice. In homozygous ERKO mice, mammary glands are underdeveloped, with rudimentary ducts con®ned to the nipple area (Lubahn et al, 1993). The presence of the Wnt-1 transgene stimulated hyperplastic ductal growth in ERKO mice, and the females developed mammary tumors at twice the age of Wnt-1 TG females with one or two intact ERa genes (Bocchinfuso et al, 1999).…”

Section: Hormonal and Stromal In¯uences On Wnt-1-induced Hyperplasia mentioning

confidence: 99%

Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer

2000

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Wnt-1 was ®rst identi®ed as a protooncogene activated by viral insertion in mouse mammary tumors. Transgenic expression of this gene using a mouse mammary tumor virus LTR enhancer causes extensive ductal hyperplasia early in life and mammary adenocarcinomas in approximately 50% of the female transgenic (TG) mice by 6 months of age. Metastasis to the lung and proximal lymph nodes is rare at the time tumors are detected but frequent after the removal of the primary neoplasm. The potent mitogenic e ect mediated by Wnt-1 expression does not require estrogen stimulation; tumors form after an increased latency in estrogen receptor a-null mice. Several genetic lesions, including inactivation of p53 and over-expression of Fgf-3, collaborate with Wnt-1 in leading to mammary tumors, but loss of Sky and inactivation of one allele of Rb do not a ect the rate of tumor formation in Wnt-1 TG mice.

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“…ERα knockout (αERKO) mice and their wild-type counterparts (C57/BL6/J background) (Lubahn et al 1993) were ovariectomized at 8 weeks of age. After 2 weeks, the ovariectomized mice were injected with 17β-oestradiol (Sigma; 5 µg/kg b.w.)…”

Section: Animalsmentioning

confidence: 99%

Genome‐wide analysis of changes in early gene expression induced by oestrogen

et al. 2002

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Background: The sex hormone 17β‐oestradiol (E2) has profound effects on many aspects of reproduction, development, as well as behaviour. Although the oestrogen receptor is well characterized on a molecular level, relatively few genes affected by E2 have been identified, and the mechanisms underlying the physiological changes caused by E2 are largely unknown. In order to identify oestrogen‐regulated genes in vivo, early uterine gene expression profiles were developed using DNA microarrays. Results: Ovariectomized mice were exposed to 17β‐oestradiol for 6 h, and mRNA expression analysis for 9977 genes was performed. Although a large number of genes was affected by oestrogen administration, the genes that showed higher reproducibility in repetitive experiments were selected and further examined. For most of the selected genes, expression was induced in a dose‐dependent manner, and gene expression was not altered following oestrogen treatment in oestrogen receptor‐α (ERα)‐deficient mice. In combination with the estimation of gene expression levels using quantitative PCR, it was revealed that multiple genes related to sterol biosynthesis, tRNA synthesis, RNA processing, and growth signalling were activated. Based on the microarray data, we selected additional genes related to sterol biosynthesis and tRNA synthesis and confirmed that these genes are also activated by oestrogen. Conclusion: Genes suggesting a basis for the drastic uterotrophic effect observed several days following oestrogen administration were identified. These findings not only reveal the diverse effect of oestrogen signalling on transcript levels in vivo but also demonstrate the ability of DNA microarrays to identify cellular pathways affected by oestrogen.

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Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene.

Cited by 1,690 publications

References 34 publications

The faah gene is the first direct target of estrogen in the testis: role of histone demethylase LSD1

The faah gene is the first direct target of estrogen in the testis: role of histone demethylase LSD1

Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer

Genome‐wide analysis of changes in early gene expression induced by oestrogen

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