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Estrogen Signaling in Arcuate Kiss1 Neurons Suppresses a Sex-Dependent Circuit That Promotes Dense Strong Bones in Female Mice

ABSTRACT: Purpose: To characterize the estrogen receptor α (ESR1)-dependent transcriptome of neurons in the arcuate nucleus that regulate female bone density

ORGANISM(S): Mus musculus

PROVIDER: GSE122291 | GEO | 2019/01/17

REPOSITORIES: GEO

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Estrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones.

Project description:Central estrogen signaling coordinates energy expenditure, reproduction, and in concert with peripheral estrogen impacts skeletal homeostasis in females. Here, we ablate estrogen receptor alpha (ER?) in the medial basal hypothalamus and find a robust bone phenotype only in female mice that results in exceptionally strong trabecular and cortical bones, whose density surpasses other reported mouse models. Stereotaxic guided deletion of ER? in the arcuate nucleus increases bone mass in intact and ovariectomized females, confirming the central role of estrogen signaling in this sex-dependent bone phenotype. Loss of ER? in kisspeptin (Kiss1)-expressing cells is sufficient to recapitulate the bone phenotype, identifying Kiss1 neurons as a critical node in this powerful neuroskeletal circuit. We propose that this newly-identified female brain-to-bone pathway exists as a homeostatic regulator diverting calcium and energy stores from bone building when energetic demands are high. Our work reveals a previously unknown target for treatment of age-related bone disease.

| S-EPMC6329772 | biostudies-literature

Estrogen Signaling in Arcuate Kiss1 Neurons Suppresses a Sex-Dependent Circuit That Promotes Dense Strong Bones in Female Mice

Project description:Estrogen Signaling in Arcuate Kiss1 Neurons Suppresses a Sex-Dependent Circuit That Promotes Dense Strong Bones in Female Mice

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Estrogen Receptor alpha DNA-binding in the arcuate and AVPV nuclei of the hypothalamus in female mice

Project description:Coupling the release of pituitary hormones to the developmental stage of the oocyte is essential for female fertility. It requires estrogen to restrain kisspeptin (Kiss1) neuron pulsatility in the arcuate hypothalamic nucleus, while also exerting a surge-like effect on Kiss1 neuron activity in the AVPV hypothalamic nucleus. However, a mechanistic basis for this region-specific effect has remained elusive. Here, we provide functional insight into hypothalamic estrogen sensing by analyzing estrogen receptor alpha (ERα/ESR1) DNA binding events in the arcuate and AVPV nuclei of the hypothalamus in female mice.

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Arcuate organoid cells

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The Arcuate Estrogenome: Estrogen Response Element-dependent and -independent Signaling of ERα

Project description:We used three genotypes of mice: 1) wild-type, 2) KIKO (knock in/knock out), which lack a functional ERE-binding domain, and 3) ERKO (total ERα knockout) to determine ERE-dependent and -independent signaling of E2 in the arcuate nucleus of mice.

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Arcuate organoid cells

Project description:We report the application of bulk and single-cell RNAseq profiling to arcuate organoid cells

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Sex-specific epigenetic development in the mouse hypothalamic arcuate nucleus pinpoints human genomic regions associated with body mass index

Project description:Developmental epigenetic study of DNA methylation in arcuate nucleus neurons and glia.

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Transcriptomic response of the arcuate nucleus to oral corticosterone treatment

Project description:Glucocorticoids (GCs) are widely prescribed to treat inflammatory and autoimmune conditions. However, patients often develop adverse metabolic effects, including hyperphagia, obesity, and hyperglycemia.The arcuate nucleus has an established role in the central control of energy balance. In this study we examined the transcriptomic response of the arcuate nucleus to oral corticosterone treatment. Gene expression changes were measured after 2 days and 4 weeks of Cort treatment in ad libitum fed C57BL6/J mice.

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A Molecular Census of Arcuate Hypothalamus and Median Eminence Cell Types

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Elacestrant demonstrates strong anti-estrogenic activity in PDX models of estrogen receptor positive endocrine-resistant and fulvestrant-resistant breast cancer

Project description:Human breast cancer cell lines were cultured in phenol red-free RPMI1640 medium supplemented with 10% fetal bovine serum and 1nM E2. All cell lines were banked in multiple aliquots to reduce the risk of phenotypic drift and identity confirmed using STR. Cells were routinely screened for mycoplasma contamination. Long-term E deprived (LTED) cells modelling resistance to an AI were derived from all parental cell lines as previously described. Two models of MCF7-LTED cells were available: one harbouring a Y537C mutation in ESR1 and the other with wt-ESR1. SUM44-LTED was shown to harbour a natural heterozygous ESR1Y537S mutation. Elacestrant resistant cell lines were generated by growing parental cells (MCF7-LTEDY537C) long-term in the presence of RPMI1640 containing 10% DCC + 0.1nM E2 + 1μM elacestrant. All cell lines were stripped of steroids for 48-72 hours prior to the start of experiments.

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