Generation of an all-exon Esr2 deleted mouse line: Effects on fertility

Antonson, Per; Apolinário, Letícia Montanholi; Shamekh, Mohamed M.; Humire, Patricia; Poutanen, Matti; Ohlsson, Claes; Nalvarte, Ivan; Gustafsson, Jan Åke

doi:10.1016/j.bbrc.2020.06.063

Cited by 17 publications

(26 citation statements)

References 30 publications

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“…Studies on knockout (KO) mouse models have shown that mice lacking ERα have aberrant sexual behavior, linked to hypothalamic actions of this receptor [ 52 ], and that these mice have unaffected spatial learning but impaired performance in the passive avoidance tests, suggesting a role for ERα in non-hippocampal dependent (or non-spatial dependent) memory [ 53 ]. On the other hand, ERβ KO mice have normal sexual behavior (although female ERβ KO mice have reduced fertility [ 54 ]), impaired spatial learning [ 55 ], increased locomotor activity [ 6 ], and increased anxiety behavior [ 56 ], but not impaired performance in the passive avoidance test [ 53 ], suggesting that ERα and ERβ have some degree of complementary functions in cognition. Furthermore, selective ERβ activation can modulate microglia-mediated neuroinflammation [ 57 ] and protects oligodendrocytes against myelination damage in a mouse model of multiple sclerosis [ 58 ].…”

Section: Estrogen Receptors In the Brainmentioning

confidence: 99%

Estrogen receptors and the aging brain

Maioli

Leander

Nilsson

et al. 2021

Essays in Biochemistry

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The female sex hormone estrogen has been ascribed potent neuroprotective properties. It signals by binding and activating estrogen receptors that, depending on receptor subtype and upstream or downstream effectors, can mediate gene transcription and rapid non-genomic actions. In this way, estrogen receptors in the brain participate in modulating neural differentiation, proliferation, neuroinflammation, cholesterol metabolism, synaptic plasticity, and behavior. Circulating sex hormones decrease in the course of aging, more rapidly at menopause in women, and slower in men. This review will discuss what this drop entails in terms of modulating neuroprotection and resilience in the aging brain downstream of spatiotemporal estrogen receptor alpha (ERα) and beta (ERβ) signaling, as well as in terms of the sex differences observed in Alzheimer’s disease (AD) and Parkinson’s disease (PD). In addition, controversies related to ER expression in the brain will be discussed. Understanding the spatiotemporal signaling of sex hormones in the brain can lead to more personalized prevention strategies or therapies combating neurodegenerative diseases.

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Section: Estrogen Receptors In the Brainmentioning

confidence: 99%

Estrogen receptors and the aging brain

Maioli

Leander

Nilsson

et al. 2021

Essays in Biochemistry

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“…A mutation in ESR2 resulted in a lack of puberty and complete failure of the ovarian function in women [ 101 ]. In mice, a mutated ESR2 can cause infertility [ 102 ]. Still, one cannot jump to conclusions, because the same peak SNP could suggest another gene: MTHFD1 .…”

Section: Discussionmentioning

confidence: 99%

Meta-Analysis of Heifer Traits Identified Reproductive Pathways in Bos indicus Cattle

Tahir

Porto-Neto

Gondro

et al. 2021

Genes

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Fertility traits measured early in life define the reproductive potential of heifers. Knowledge of genetics and biology can help devise genomic selection methods to improve heifer fertility. In this study, we used ~2400 Brahman cattle to perform GWAS and multi-trait meta-analysis to determine genomic regions associated with heifer fertility. Heifer traits measured were pregnancy at first mating opportunity (PREG1, a binary trait), first conception score (FCS, score 1 to 3) and rebreeding score (REB, score 1 to 3.5). The heritability estimates were 0.17 (0.03) for PREG1, 0.11 (0.05) for FCS and 0.28 (0.05) for REB. The three traits were highly genetically correlated (0.75–0.83) as expected. Meta-analysis was performed using SNP effects estimated for each of the three traits, adjusted for standard error. We identified 1359 significant SNPs (p-value < 9.9 × 10−6 at FDR < 0.0001) in the multi-trait meta-analysis. Genomic regions of 0.5 Mb around each significant SNP from the meta-analysis were annotated to create a list of 2560 positional candidate genes. The most significant SNP was in the vicinity of a genomic region on chromosome 8, encompassing the genes SLC44A1, FSD1L, FKTN, TAL2 and TMEM38B. The genomic region in humans that contains homologs of these genes is associated with age at puberty in girls. Top significant SNPs pointed to additional fertility-related genes, again within a 0.5 Mb region, including ESR2, ITPR1, GNG2, RGS9BP, ANKRD27, TDRD12, GRM1, MTHFD1, PTGDR and NTNG1. Functional pathway enrichment analysis resulted in many positional candidate genes relating to known fertility pathways, including GnRH signaling, estrogen signaling, progesterone mediated oocyte maturation, cAMP signaling, calcium signaling, glutamatergic signaling, focal adhesion, PI3K-AKT signaling and ovarian steroidogenesis pathway. The comparison of results from this study with previous transcriptomics and proteomics studies on puberty of the same cattle breed (Brahman) but in a different population identified 392 genes in common from which some genes—BRAF, GABRA2, GABR1B, GAD1, FSHR, CNGA3, PDE10A, SNAP25, ESR2, GRIA2, ORAI1, EGFR, CHRNA5, VDAC2, ACVR2B, ORAI3, CYP11A1, GRIN2A, ATP2B3, CAMK2A, PLA2G, CAMK2D and MAPK3—are also part of the above-mentioned pathways. The biological functions of the positional candidate genes and their annotation to known pathways allowed integrating the results into a bigger picture of molecular mechanisms related to puberty in the hypothalamus–pituitary–ovarian axis. A reasonable number of genes, common between previous puberty studies and this study on early reproductive traits, corroborates the proposed molecular mechanisms. This study identified the polymorphism associated with early reproductive traits, and candidate genes that provided a visualization of the proposed mechanisms, coordinating the hypothalamic, pituitary, and ovarian functions for reproductive performance in Brahman cattle.

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“…Several lines of Esr2-knockout mice have been developed to determine the physiological functions of ESR2 [7,23,36,40]. Disruption of ESR2 functions generally results in female fertility defects due to failure of ovulation [2,7,23]. Based on an assumption of wide distribution of mouse Esr2 transcripts and ESR2 proteins, phenotypes of Esr2knockout mice have been evaluated in multiple mouse organs and tissues, such as adipose tissues [27], immune tissues [9,19], lung [28,33], mammary gland [4,10,40], prostate [16,40,42], and uterus [39,41].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a mouse line with complete deletion of all Esr2 exons was generated [40]. Antonson et al [2] demonstrated that the PPZ0506 antibody was applicable for immunoblot detection of mouse ESR2 proteins in wild-type mice with appropriate negative references prepared from these all-Esr2-exon-deleted mice. As immunoreactive specificity of the PPZ0506 antibody against mouse ESR2 proteins was previously validated [2,17], it would be worthwhile to optimize immunohistochemical methodology for mouse ESR2 proteins and determine organ-specific localization profiles using this well-validated antibody.…”

Section: Introductionmentioning

confidence: 99%

Optimized Mouse-on-mouse Immunohistochemical Detection of Mouse ESR2 Proteins with PPZ0506 Monoclonal Antibody

Ozawa

Hattori

Higo

et al. 2022

Acta Histochem. Cytochem.

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Despite the physiological significance of ESR2, a lack of well-validated detection systems for ESR2 proteins has hindered progress in ESR2 research. Thus, recent identification of a specific anti-human ESR2 monoclonal antibody (PPZ0506) and its specific cross-reactivity against mouse and rat ESR2 proteins heightened momenta toward development of appropriate immunohistochemical detection systems for rodent ESR2 proteins. Building upon our previous optimization of ESR2 immunohistochemical detection in rats using PPZ0506, in this study, we further aimed to optimize mouse-on-mouse immunohistochemical detection using PPZ0506. Our assessment of several staining conditions using paraffin-embedded ovary sections revealed that intense heat-induced antigen retrieval, appropriate blocking, and appropriate antibody dilutions were necessary for optimization of mouse-on-mouse immunohistochemistry. Subsequently, we applied the optimized immunostaining method to determine expression profiles of mouse ESR2 proteins in peripheral tissues and brain subregions. Our analyses revealed more localized distribution of mouse ESR2 proteins than previously assumed. Moreover, comparison of these results with those obtained in humans and rats using PPZ0506 revealed interspecies differences in ESR2 expression. We expect that our optimized methodology for immunohistochemical staining of mouse ESR2 proteins will help researchers to solve multiple lines of controversial evidence concerning ESR2 expression.

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Generation of an all-exon Esr2 deleted mouse line: Effects on fertility

Cited by 17 publications

References 30 publications

Estrogen receptors and the aging brain

Estrogen receptors and the aging brain

Meta-Analysis of Heifer Traits Identified Reproductive Pathways in Bos indicus Cattle

Optimized Mouse-on-mouse Immunohistochemical Detection of Mouse ESR2 Proteins with PPZ0506 Monoclonal Antibody

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