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Regulation of NKB Pathways and Their Roles in the Control of Kiss1 Neurons in the Arcuate Nucleus of the Male Mouse
Open accessAbstract
Kisspeptin (Kiss1) and neurokinin B (NKB) (encoded by the Kiss1 and Tac2 genes, respectively) are indispensable for reproduction. In the female of many species, Kiss1 neurons in the arcuate nucleus (ARC) coexpress dynorphin A and NKB. Such cells have been termed Kiss1/NKB/Dynorphin (KNDy) neurons, which are thought to mediate the negative feedback regulation of GnRH/LH secretion by 17β-estradiol. However, we have less knowledge about the molecular physiology and regulation of Kiss1/Kiss1-expressing neurons in the ARC of the male. Our work focused on the adult male mouse, where we sought evidence for coexpression of these neuropeptides in cells in the ARC, assessed the role of Kiss1 neurons in negative feedback regulation of GnRH/LH secretion by testosterone (T), and investigated the action of NKB on KNDy and GnRH neurons. Results showed that 1) the mRNA encoding Kiss1, NKB, and dynorphin are coexpressed in neurons located in the ARC; 2) Kiss1 and dynorphin A mRNA are regulated by T through estrogen and androgen receptor-dependent pathways; 3) senktide, an agonist for the NKB receptor (neurokinin 3 receptor, encoded by Tacr3), stimulates gonadotropin secretion; 4) KNDy neurons express Tacr3, whereas GnRH neurons do not; and 5) senktide activates KNDy neurons but has no discernable effect on GnRH neurons. These observations corroborate the putative role for KNDy neurons in mediating the negative feedback effects of T on GnRH/LH secretion and provide evidence that NKB released from KNDy neurons is part of an auto-feedback loop that generates the pulsatile secretion of Kiss1 and GnRH in the male.
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“Complete coexpression of kisspeptin, NKB and dynorphin is not always found (Hrabovszky et al., 2012; Navarro et al., 2011), but this issue is complicated by limitations in the sensitivity of detection (Ruka et al., 2013) and differential expression depending on developmental stage (Gill et al., 2012) or physiological state of the animal (Foradori et al., 2005; Navarro et al., 2011; Rance and Bruce”
From Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: A novel hypothesis on the mechanism of hot flushes (2013) · cites this paper as Navarro et al., 2011
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The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859
A role for kisspeptins in the regulation of gonadotropin secretion in the mouse
Gottsch, M. L., Cunningham, M. J., Smith, J. T., Popa, S. M., Acohido, B. V., Crowley, W. F., Seminara, S., Clifton, D. K., & Steiner, R. A. (2004) · Endocrinology · doi:10.1210/en.2004-0431 · Cited by 1,161
Self-citationRegulation of Kiss1 gene expression in the brain of the female mouse
Smith, J. T., Cunningham, M. J., Rissman, E. F., Clifton, D. K., & Steiner, R. A. (2005) · Endocrinology · doi:10.1210/en.2005-0488 · Cited by 1,102
Self-citationHan, S.-K., Gottsch, M. L., Lee, K. J., Popa, S. M., Smith, J. T., Jakawich, S. K., Clifton, D. K., Steiner, R. A., & Herbison, A. E. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.3328-05.2005 · Cited by 1,036
Self-citationTopaloglu, A. K., Reimann, F., Guclu, M., Yalin, A. S., Kotan, L. D., Porter, K. M., Serin, A., Mungan, N. O., Cook, J. R., Ozbek, M. N., et al. (2009) · Nature Genetics · doi:10.1038/ng.306 · Cited by 961
Irwig, M. S., Fraley, G. S., Smith, J. T., Acohido, B. V., Popa, S. M., Cunningham, M. J., Gottsch, M. L., Clifton, D. K., & Steiner, R. A. (2004) · Neuroendocrinology · doi:10.1159/000083140 · Cited by 930
Self-citationKisspeptin Signaling in the Brain
Oakley, A. E., Clifton, D. K., & Steiner, R. A. (2009) · Endocrine Reviews · doi:10.1210/er.2009-0005 · Cited by 842
Self-citationNavarro, V. M., Gottsch, M. L., Chavkin, C., Okamura, H., Clifton, D. K., & Steiner, R. A. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.1569-09.2009 · Cited by 779
Self-citationLehman, M. N., Coolen, L. M., & Goodman, R. L. (2010) · Endocrinology · doi:10.1210/en.2010-0022 · Cited by 768
Differential Regulation of KiSS-1 mRNA Expression by Sex Steroids in the Brain of the Male Mouse
Smith, J. T., Lemko, H. M. D., Stoll, E. A., Gottsch, M. L., Braun, R. E., Eacker, S. M., Clifton, D. K., & Steiner, R. A. (2005) · Endocrinology · doi:10.1210/en.2005-0323 · Cited by 717
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Metadata
- Authors
- Navarro, V. M., Gottsch, M. L., Wu, M., García-Galiano, D., Hobbs, S. J., Bosch, M. A., Pinilla, L., Clifton, D. K., Dearth, A., Ronnekleiv, O. K., Braun, R. E., Palmiter, R. D., Tena-Sempere, M., Alreja, M., & Steiner, R. A.
- Affiliations
- University of Washington (US)
- Yale University (US)
- Instituto Maimónides de Investigación Biomédica de Córdoba (ES)
- Oregon Health & Science University (US)
- Jackson Laboratory (US)
- Department of Physiology and Pharmacology (M.A.B., O.K.R.), Oregon Health and Science University, Portland, Oregon 97239
- Department of Cell Biology, Physiology, and Immunology (D.G.-G., L.P., M.T.-S.), Córdoba 14004, Spain
- Corresponding author
- Navarro, V. M.
- ORCID
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2011-09-13
- Volume
- 152
- Issue
- 11
- Pages
- 4265-4275
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC3198996
- OpenAlex
- W2035954641
- Cited by
- 254
- References
- 41
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 11 · 2023: 6 · 2022: 7 · 2021: 18 · 2020: 12 · 2019: 17 · 2018: 19 · 2017: 16 · 2016: 24 · 2015: 15 · 2014: 28 · 2013: 33 · 2012: 28
- FWCI
- 32.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Institutes of Health (5u54hd012629-31)
- National Institute of Mental Health (MH 61465, R01MH061465)
- National Institute on Drug Abuse (K05DA020570, R01DA016898, KO5-DA020570)
- National Institute of Neurological Disorders and Stroke (R01NS043330)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD049651, U54-HD-12629, U54HD-012629)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
- Keywords
- kisspeptin, neurokinin B, dynorphin A, KNDy neurons, arcuate nucleus, GnRH neurons, testosterone, negative feedback regulation, neurokinin-3 receptor, senktide, pulsatile gonadotropin secretion, male reproduction
- MeSH terms
- Animals, Arcuate Nucleus of Hypothalamus, Dynorphins, Gonadotropin-Releasing Hormone, Male, Neurons, Receptors, Estrogen, Receptors, Progesterone, Neurokinin B, Signal Transduction, Feedback, Physiological, Mice, Kisspeptins
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