Regulation of Kiss1 and Dynorphin Gene Expression in the Murine Brain by Classical and Nonclassical Estrogen Receptor Pathways
Open accessAbstract
Kisspeptin is a product of the Kiss1 gene and is expressed in the forebrain. Neurons that express Kiss1 play a crucial role in the regulation of pituitary luteinizing hormone secretion and reproduction. These neurons are the direct targets for the action of estradiol-17β (E 2 ), which acts via the estrogen receptor α isoform (ERα) to regulate Kiss1 expression. In the arcuate nucleus (Arc), where the dynorphin gene ( Dyn ) is expressed in Kiss1 neurons, E 2 inhibits the expression of Kiss1 mRNA. However, E 2 induces the expression of Kiss1 in the anteroventral periventricular nucleus (AVPV). The mechanism for differential regulation of Kiss1 in the Arc and AVPV by E 2 is unknown. ERα signals through multiple pathways, which can be categorized as either classical, involving the estrogen response element (ERE), or nonclassical, involving ERE-independent mechanisms. To elucidate the molecular basis for the action of E 2 on Kiss1 and Dyn expression, we studied the effects of E 2 on Kiss1 and Dyn mRNAs in the brains of mice bearing targeted alterations in the ERα signaling pathways. We found that stimulation of Kiss1 expression by E 2 in the AVPV and inhibition of Dyn in the Arc required an ERE-dependent pathway, whereas the inhibition of Kiss1 expression by E 2 in the Arc involved ERE-independent mechanisms. Thus, distinct ERα signaling pathways can differentially regulate the expression of identical genes across different brain regions, and E 2 can act within the same neuron through divergent ERα signaling pathways to regulate different neurotransmitter genes.
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Both kisspeptin populations have ERα and low ERβ but respond differently to E2 via ERE-dependent and ERE-independent mechanisms.
“Both populations of kisspeptin neurons express ERα (with low ERβ expression) but respond differentially to E2 through ERE-dependent and ERE-independent mechanisms44,45.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [45]
The Abstract and Discussion report that E2 induces Kiss1 in the AVPV through an ERE-dependent ERα pathway but inhibits Kiss1 in the arcuate nucleus through an ERE-independent pathway. The Introduction says regulation in both regions requires ERα. The passages do not establish the claim that both populations have low ERβ expression (page numbers are unavailable in our copy). (LLM, conf=0.85)
Experimental — accuracy not yet measuredNeurokinin B and dynorphin, co-expressed with kisspeptin in ARC KNDy neurons, are downregulated by E2 via ERα-mediated ERE-dependent mechanisms.
“Neurokinin B and dynorphin, co-expressed with kisspeptin (KNDy neurons) in the ARC nucleus and vital components of the GnRH pulse generator, are also downregulated by E2 but through ERα-mediated, ERE-dependent mechanisms44,45.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [45]
The Discussion reports that E2 inhibits dynorphin (Dyn) expression in the mouse arcuate nucleus through an ERE-dependent ERα pathway. Our copy does not report that neurokinin B is downregulated by this pathway; it mentions neurokinin B in the title of a cited study in the References. The Discussion also says the function of dynorphin in these neurons remains a mystery, rather than establishing it as a vital component of the GnRH pulse generator. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn AVPV/PeN kisspeptin neurons, E2 stimulates Kiss1 mRNA and kisspeptin synthesis via ERα-mediated ERE-dependent mechanisms.
“In AVPV/PeN kisspeptin neurons, Kiss1 mRNA expression and kisspeptin synthesis are stimulated by E2 through ERα-mediated, ERE-dependent mechanisms45.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [45]
The Results section, “E2 Regulation of Kiss1 mRNA in the AVPV” (page unavailable), reports higher Kiss1 mRNA expression with E2, and the Discussion says ERα-mediated, ERE-dependent regulation is suggested by the findings. The paper measures Kiss1 mRNA, not kisspeptin synthesis, and the cited passages address the AVPV rather than explicitly the AVPV/PeN. (LLM, conf=0.88)
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References 48 · Cited by 195
- Authors
- Gottsch, M. L., Navarro, V. M., Zhao, Z., Glidewell-Kenney, C., Weiss, J., Jameson, J. L., Clifton, D. K., Levine, J. E., & Steiner, R. A.
- Affiliations
- University of Washington (US)
- Northwestern University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-07-22
- Volume
- 29
- Issue
- 29
- Pages
- 9390-9395
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2819182
- OpenAlex
- W2110656884
- Cited by
- 195
- References
- 48
- Citations by year
- 2025: 5 · 2024: 4 · 2023: 7 · 2022: 12 · 2021: 10 · 2020: 6 · 2019: 8 · 2018: 18 · 2017: 13 · 2016: 12 · 2015: 17 · 2014: 18 · 2013: 13 · 2012: 20
- FWCI
- 20.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Washington
- National Institutes of Health (5u54hd012629-31)
- National Institute of Child Health and Human Development
- Office of Research on Women's Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD049651, R01 HD 27142, P50 HD44405, P50HD044405, P01HD021921, U54-HD-12629, U54HD-012629, R01HD027142, P01HD21921)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- KISS1, kisspeptin, dynorphin, estrogen receptor alpha, estradiol, estrogen response element, arcuate nucleus, anteroventral periventricular nucleus, forebrain, luteinizing hormone secretion, reproduction, gene expression regulation
- MeSH terms
- Animals, Arcuate Nucleus of Hypothalamus, Brain, Dynorphins, Estradiol, Estrogens, Female, Gene Expression Regulation, Luteinizing Hormone, Mice, Transgenic, Neurons, Proteins, RNA, Messenger, Signal Transduction, Anterior Thalamic Nuclei, Midline Thalamic Nuclei, Estrogen Receptor alpha, Mice, Gene Knock-In Techniques, Kisspeptins
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