Phosphorylation site S122 in estrogen receptor α has a tissue‐dependent role in female mice

Ohlsson, Claes; Gustafsson, Kristian; Farman, Helen H; Henning, Petra; Lionikaite, Vikte; Movérare‐Skrtic, Sofia; Sjögren, Klara; Törnqvist, Anna E.; Andersson, Annica; Islander, Ulrika; Bernardi, Angelina I.; Poutanen, Matti; Chambon, Pierre; Lagerquist, Marie K

doi:10.1096/fj.201901376rr

Cited by 7 publications

(12 citation statements)

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“…Thus, manipulation of phosphorylation sites 216 and 541 in the murine ERα results in similar effects on body weight in females and males. Interestingly, in our model, the lower body weight observed in S122A males compared to littermate controls is opposite to what we reported for the female S122A mice, which had increased body weight compared to littermate controls 34 . These results suggest that phosphorylation of site S122 in ERα might be involved in establishment of gender difference in body weight in mice.…”

Section: Discussioncontrasting

confidence: 99%

“…Since ERα signaling is involved in the sex steroid feedback regulation in both males and females 22 , 38 , 39 , we measured serum levels of sex hormones. There were no significant differences in serum sex steroid levels between S122A and WT male mice, similarly as seen in females 34 , suggesting that the sex steroid feedback is normal in both female and male mice lacking phosphorylation site S122 in ERα. Interestingly, when analysing older, middle-aged males, there was a significant decrease in body weight in S122A compared to WT mice.…”

Section: Discussionmentioning

confidence: 77%

“…Interestingly, the inability of the human ERα to be phosphorylated at site 118 leads to decreased estradiol‐induced gene transcription in some 26 but not all 33 cell‐types, suggesting that the importance of this phosphorylation site may differ in a tissue‐dependent manner. We recently investigated the role of ERα phosphorylation site S122 in vivo in female mice, using a novel S122A genetic mouse model that lacks the ability to phosphorylate site 122 of ERα, and reported that the S122A mutation selectively affects the metabolism in females, leading to increased fat mass and insulin levels 34 . Thus, the phosphorylation site S122 in ERα has a tissue-dependent role in vivo in females.…”

Section: Introductionmentioning

confidence: 99%

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Phosphorylation of S122 in ERα is important for the skeletal response to estrogen treatment in male mice

Gustafsson

Farman

Movérare‐Skrtic

et al. 2022

Sci Rep

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Estrogen receptor alpha (ERα) signaling has beneficial skeletal effects in males. ERα signaling also affects other tissues, and to find bone-specific treatments, more knowledge regarding tissue-specific ERα signaling is needed. ERα is subjected to posttranslational modifications, including phosphorylation, which can influence ERα function in a tissue-specific manner. To determine the importance of phosphorylation site S122 (corresponding to human ERα site S118) for the skeleton and other tissues, male mice with a S122A mutation were used. Total areal bone mineral density was similar between gonadal intact S122A and WT littermates followed up to 12 months of age, and weights of estrogen-responsive organs normalized for body weight were unchanged between S122A and WT males at both 3 and 12 months of age. Interestingly, 12-month-old S122A males had decreased body weight compared to WT. To investigate if site S122 affects the estrogen response in bone and other tissues, 12-week-old S122A and WT males were orchidectomized (orx) and treated with estradiol (E2) or placebo pellets for four weeks. E2 increased cortical thickness in tibia in both orx WT (+ 60%, p < 0.001) and S122A (+ 45%, p < 0.001) males. However, the E2 effect on cortical thickness was significantly decreased in orx S122A compared to WT mice (− 24%, p < 0.05). In contrast, E2 affected trabecular bone and organ weights similarly in orx S122A and WT males. Thus, ERα phosphorylation site S122 is required for a normal E2 response specifically in cortical bone in male mice, a finding that may have implications for development of future treatments against male osteoporosis.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

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Phosphorylation of S122 in ERα is important for the skeletal response to estrogen treatment in male mice

Gustafsson

Farman

Movérare‐Skrtic

et al. 2022

Sci Rep

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“…E2 was injected every 4 days to resemble the length of the estrus cycle in mice 24 . Two vehicles for dissolving E2 were tested: miglyol is described as an inert oil used for slow and sustained absorption of the drug from the oily pocket created after the injection in the subcutaneous area; PBS is used for faster absorption 25,26 .…”

Section: Discussionmentioning

confidence: 99%

Pulsed administration for physiological estrogen replacement in mice

et al. 2021

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Estrogens are important regulators of body physiology and have major effects on metabolism, bone, the immune- and central nervous systems. The specific mechanisms underlying the effects of estrogens on various cells, tissues and organs are unclear and mouse models constitute a powerful experimental tool to define the physiological and pathological properties of estrogens. Menopause can be mimicked in animal models by surgical removal of the ovaries and replacement therapy with 17β-estradiol in ovariectomized (OVX) mice is a common technique used to determine specific effects of the hormone. However, these studies are complicated by the non-monotonic dose-response of estradiol, when given as therapy. Increased knowledge of how to distribute estradiol in terms of solvent, dose, and administration frequency, is required in order to accurately mimic physiological conditions in studies where estradiol treatment is performed. In this study, mice were OVX and treated with physiological doses of 17β-estradiol-3-benzoate (E2) dissolved in miglyol or PBS. Subcutaneous injections were performed every 4 days to resemble the estrus cycle in mice. Results show that OVX induces an osteoporotic phenotype, fat accumulation and impairment of the locomotor ability, as expected. Pulsed administration of physiological doses of E2 dissolved in miglyol rescues the phenotypes induced by OVX. However, when E2 is dissolved in PBS the effects are less pronounced, possibly due to rapid wash out of the steroid.

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“…However, it is worthy to note that most of functional studies have been performed without differentiating ERα splice variants and therefore, it remains largely unknown how these ERα variants differentially mediate the physiological and pathological roles of E2 (8). A few exceptions include genetic mouse models of post-translation modifications in a phosphorylation site or palmitoylation site of ERα (26,27). Since exons missing in a certain transcript variant are shared by other splice variants and genomic cis elements regulating splice variant expressions are largely unknown, in vivo genetic studies for specific physiological functions of splice variants have been extremely difficult.…”

Section: Introductionmentioning

confidence: 99%

Hypomorphism of a novel long ERα isoform causes severe reproductive dysfunctions in female mice

Saito

Dickey

Rodeghiero

et al. 2022

Preprint

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Estrogen receptor alpha (ERα)-mediated estrogen signaling play a pivotal role in both reproductive and non-reproductive functions. Transcriptional regulation of ERα gene is highly complex, with multiple transcript variants being differentially produced across the tissues. However, tissue-specific variation and physiological specificity of the ERα variants are not yet fully understood. In an attempt to generate a Cre-dependently restorable ERα-null mice for functional investigation of the genetic sufficiency, we unexpectedly produced ERα hypomorphic mice with biased downregulation of a previously unappreciated long ERα isoform that is enriched in the female reproductive organs (uterus and ovaries) and the pituitary but minimally expressed in the brain. Female homozygous mutant mice were capable of pregnancy but displayed irregular estrus cycle and rarely maintained alive newborns without significant morphological and pathological changes in reproductive system and the disruption of body weight homeostasis, indicating the vital role of this long isoform in female reproductive function. Collectively, our results define a tissue-specifically enriched long ERα isoform and its preferential role in female reproductive function over body weight homeostasis.

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Phosphorylation site S122 in estrogen receptor α has a tissue‐dependent role in female mice

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 7 publications

References 82 publications

Phosphorylation of S122 in ERα is important for the skeletal response to estrogen treatment in male mice

Phosphorylation of S122 in ERα is important for the skeletal response to estrogen treatment in male mice

Pulsed administration for physiological estrogen replacement in mice

Hypomorphism of a novel long ERα isoform causes severe reproductive dysfunctions in female mice

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