Visualizing estrogen receptor-α-expressing neurons using a new ERα-ZsGreen reporter mouse line

Saito, Kenji; He, Yanlin; Yan, Xiao; Yang, Yongjie; Wang, Chunmei; Xu, Pingwen; Hinton, Antentor; Shu, Gang; Yu, Likai; Tong, Qingchun; Xu, Yong

doi:10.1016/j.metabol.2015.12.011

Cited by 29 publications

(32 citation statements)

References 36 publications

(50 reference statements)

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“…To further test the responsiveness of POMC neurons to estrogenic signals, we crossed a recently generated ERα-ZsGreenmouse allele 42 with the control (POMC-CreER T2 / Rosa26-tdTOMATO) mice and mutant (POMC-CreER T2 / TAp63 fl/fl /Rosa26-tdTOMATO) mice, and performed electrophysiological recordings in ERα-positive POMC neurons (double labeled by ZsGreen and TOMATO, Fig. 6h).…”

Section: Resultsmentioning

confidence: 99%

TAp63 contributes to sexual dimorphism in POMC neuron functions and energy homeostasis

Wang¹,

He²,

Xu³

et al. 2018

ESPE

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Sexual dimorphism exists in energy balance, but the underlying mechanisms remain unclear. Here we show that the female mice have more pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of hypothalamus than males, and female POMC neurons display higher neural activities, compared to male counterparts. Strikingly, deletion of the transcription factor, TAp63, in POMC neurons confers "male-like" diet-induced obesity (DIO) in female mice associated with decreased POMC neural activities; but the same deletion does not affect male mice. Our results indicate that TAp63 in female POMC neurons contributes to the enhanced POMC neuron functions and resistance to obesity in females. Thus, TAp63 in POMC neurons is one key molecular driver for the sexual dimorphism in energy homeostasis.

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Section: Resultsmentioning

confidence: 99%

TAp63 contributes to sexual dimorphism in POMC neuron functions and energy homeostasis

Wang¹,

He²,

Xu³

et al. 2018

ESPE

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“…Tamoxifen is a selective estrogen receptor modulator that exerts antiproliferative effects on cancer cells through ERα (Davies et al 2011), but can exert agonistic or antagonistic effects on the different estrogen receptors depending on cell type and context (Watanabe et al 1997, Mo et al 2013. The medial basal hypothalamus is rich in estrogen receptor expression, making it a prime candidate as a tamoxifen target (Merchenthaler et al 2004, Gofflot et al 2007, Matsuda et al 2013, Saito et al 2016. Here we take the first steps to define the cell types and cellular mechanisms that mediate some of the undesirable side effects experienced by people undergoing tamoxifen therapy.…”

Section: Discussionmentioning

confidence: 99%

Hypothalamic estrogen receptor alpha mediates key side effects of tamoxifen therapy in mice

Zhang

Park

Ahn

et al. 2020

Preprint

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Adjuvant tamoxifen therapy for invasive breast cancer improves patient survival. Unfortunately, long-term treatment comes with side effects that impact health and quality of life, including hot flashes, changes in bone density, and fatigue. Partly due to a lack of proven animal models, the tissues and cell types that mediate these negative side effects are largely unknown. Here we show that mice undergoing a 28-day course of tamoxifen treatment experience dysregulation of core and skin temperature, changes in bone density, and decreased physical activity, recapitulating key aspects of the human physiological response. Single cell RNA sequencing reveals that tamoxifen treatment induces significant and widespread gene expression changes in different cell types of the hypothalamus, most strongly in neurons and ependymal cells. These expression changes are dependent on estrogen receptor alpha (ERα), as conditional knockout of ERα in the hypothalamus ablated or reversed tamoxifen-induced gene expression. Accordingly, ERα-deficient mice do not exhibit changes in thermal regulation, bone density, or movement in response to tamoxifen treatment. These findings provide mechanistic insight into the effects of tamoxifen on the hypothalamus and support a model in which hypothalamic ERα mediates several key side effects of tamoxifen therapy.

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“…The female estrus cycle has four phases that occur in a particular order (estrus, metaestrus, diestrus, and proestrus). The relative serum sex hormone concentrations (Nilsson et al, 2015) and sex hormone receptors fluctuate according to cycle phase (Mitterling et al, 2010) and vary between brain locations (Kato et al, 2013;Saito et al, 2016). The cessation of ovarian function, cyclic release of sex hormones, and termination of menses are among the elements that define the post-menopause phase of life for women.…”

Section: Discussionmentioning

confidence: 99%

“…These regions were selected based on their relevance to injury models involving the somatosensory cortex (ischemic stroke and traumatic brain injury) as well as models used to study memory impairment (hippocampus CA1 region). In addition, both regions express estrogen receptors to a different extent (Merchenthaler et al, 2004;Saito et al, 2016). One photomicrograph was acquired in each region.…”

Section: Photomicrograph Acquisition and Analysismentioning

confidence: 99%

“…Lastly, we screened for differences in inflammatory protein concentrations in the healthy brain. For additional comparison, two brain regions were included in the study that were previously shown to have high (hippocampus) or low (cortex) constitutive expression of estrogen receptors (Merchenthaler et al, 2004;Saito et al, 2016). In addition, both the cortex and hippocampus regions are relevant to a diversity of CNS injury models.…”

Section: Introductionmentioning

confidence: 99%

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Sex and regional differences in microglia morphology and complement receptor 3 are independent of constitutive neuroinflammatory protein concentrations in healthy mice

Young

Rothers

Castaneda

et al. 2018

Preprint

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Microglia are highly ramified brain phagocytes that are finely tuned to surrounding neuronal and glial activity. Combined, microglia morphology, dynamic process movement, phagocytic, and neuroinflammatory responses aid in the detection of changed neuronal function, maintenance, and restoration of neural networks during physiology and pathophysiologic conditions. An awareness of how microglia diversity in the healthy brain relates to brain region and sex differences would inform brain physiology, further delineate risk factors of central nervous system (CNS) diseases, and clarify mechanisms of dichotomous injury outcomes between men and women. Microglia morphology, complement receptor 3 (CR3), and neuroinflammatory proteins were studied in the somatosensory cortex and hippocampus CA1 among male and female (estrus, diestrus and ovarian failure) mice (C67Bl/6J, 16 weeks) to discover relationships among microglia morphology, region, sex, and neuroinflammatory environment. The human post-menopause period was modeled in mice using 4-vinylcyclohexene diepoxide injections which induced accelerated ovarian failure. Using methods to quantify ramification, shape, and complexity, we discovered differences in microglia morphologies according to brain region and sex group. Microglia endpoints, process length, and complexity were increased in the female ovarian failure group when compared to other sex groups. Microglia were smaller and less complex in the hippocampus region versus the cortex. Microglia phagocytic receptor CR3 was assessed using immunohistochemistry methods and was increased in the female diestrus cortex when compared to male and females in estrus; no sex differences were observed in the hippocampus. Neuroinflammatory protein concentrations were screened using Multiplex Luminex methods and were detected in cortex homogenates, however, no differences among the sex groups were observed. Microglia morphology and CR3 are diverse in the adult healthy Understanding sex and region specific differences in the brain's surveillance and maintenance system will provide insight into the variability of patient risk and outcomes in CNS diseases.PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.26937v1 | CC BY 4.0 Open Access |

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Visualizing estrogen receptor-α-expressing neurons using a new ERα-ZsGreen reporter mouse line

Cited by 29 publications

References 36 publications

TAp63 contributes to sexual dimorphism in POMC neuron functions and energy homeostasis

TAp63 contributes to sexual dimorphism in POMC neuron functions and energy homeostasis

Hypothalamic estrogen receptor alpha mediates key side effects of tamoxifen therapy in mice

Sex and regional differences in microglia morphology and complement receptor 3 are independent of constitutive neuroinflammatory protein concentrations in healthy mice

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