Kisspeptin–GPR54 Signaling Is Essential for Preovulatory Gonadotropin-Releasing Hormone Neuron Activation and the Luteinizing Hormone Surge
Abstract
Kisspeptin and its receptor GPR54 have recently been identified as key signaling partners in the neural control of fertility in animal models and humans. The gonadotropin-releasing hormone (GnRH) neurons represent the final output neurons of the neural network controlling fertility and are suspected to be the primary locus of kisspeptin–GPR54 signaling. Using mouse models, the present study addressed whether kisspeptin and GPR54 have a key role in the activation of GnRH neurons to generate the luteinizing hormone (LH) surge responsible for ovulation. Dual-label immunocytochemistry experiments showed that 40–60% of kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) expressed estrogen receptor α and progesterone receptors. Using an ovariectomized, gonadal steroid-replacement regimen, which reliably generates an LH surge, ∼30% of RP3V kisspeptin neurons were found to express c-FOS in surging mice compared with 0% in nonsurging controls. A strong correlation was found between the percentage of c-FOS-positive kisspeptin neurons and the percentage of c-FOS-positive GnRH neurons. To evaluate whether kisspeptin and/or GPR54 were essential for GnRH neuron activation and the LH surge, Gpr54 - and Kiss1 -null mice were examined. Whereas wild-type littermates all exhibited LH surges and c-FOS in ∼50% of their GnRH neurons, none of the mutant mice from either line showed an LH surge or any GnRH neurons with c-FOS. These observations provide the first evidence that kisspeptin–GPR54 signaling is essential for GnRH neuron activation that initiates ovulation. This broadens considerably the potential roles and therapeutic possibilities for kisspeptin and GPR54 in fertility regulation.
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Kisspeptin neurons express ERα, and the kisspeptin receptor GPR54 is expressed in GnRH neurons.
“Kisspeptin neurons have been shown to express ERα (Adachi et al., 2007; Clarkson, d’Anglemont de Tassigny, Moreno, Colledge, & Herbison, 2008; Franceschini et al., 2006) and the kisspeptin receptor GPR54 is expressed in GnRH neurons (Clements et al., 2001; Kotani et al., 2001; Muir et al., 2001; Ohtaki et al., 2001).”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Clarkson, d’Anglemont de Tassigny, Moreno, Colledge, & Herbison, 2008
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Cites
The <i>GPR54</i> Gene as a Regulator of Puberty
Seminara, S. B., Messager, S., Chatzidaki, E. E., Thresher, R. R., Acierno, J. S., Shagoury, J. K., Bo-Abbas, Y., Kuohung, W., Schwinof, K. M., Hendrick, A. G., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa035322 · Cited by 2,557 · see citing works
Self-citationHypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54
de Roux, N., Genin, E., Carel, J.-C., Matsuda, F., Chaussain, J.-L., & Milgrom, E. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1834399100 · Cited by 2,431 · cited 1× · see citing works
“Two seminal clinical studies in 2003 identified kisspeptin and its receptor GPR54 to be essential for puberty onset and normal human fertility (de Roux et al., 2003; Seminara et al., 2003).”
BackgroundThe KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system
Funes, S., Hedrick, J. A., Vassileva, G., Markowitz, L., Abbondanzo, S., Golovko, A., Yang, S., Monsma, F. J., & Gustafson, E. L. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.11.066 · Cited by 675 · see citing works
ADACHI, S., YAMADA, S., TAKATSU, Y., MATSUI, H., KINOSHITA, M., TAKASE, K., SUGIURA, H., OHTAKI, T., MATSUMOTO, H., UENOYAMA, Y., et al. (2007) · Journal of Reproduction and Development · doi:10.1262/jrd.18146 · Cited by 580 · see citing works
Smith, J. T., Clay, C. M., Caraty, A., & Clarke, I. J. (2007) · Endocrinology · doi:10.1210/en.2006-1435 · Cited by 404 · see citing works
Haywood, S. A., Simonian, S. X., van der Beek, E. M., Bicknell, R. J., & Herbison, A. E. (1999) · Endocrinology · doi:10.1210/endo.140.7.6869 · Cited by 167 · see citing works
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Kisspeptin 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 · see citing works
Oyola, M. G., & Handa, R. J. (2017) · Stress · doi:10.1080/10253890.2017.1369523 · Cited by 710 · see citing works
Control of puberty onset and fertility by gonadotropin-releasing hormone neurons
Herbison, A. E. (2016) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.70 · Cited by 515 · see citing works
Self-citationSex differences in circadian timing systems: implications for disease
Bailey, M., & Silver, R. (2014) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2013.11.003 · Cited by 348 · see citing works
GnRH signaling, the gonadotrope and endocrine control of fertility
Bliss, S. P., Navratil, A. M., Xie, J., & Roberson, M. S. (2010) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2010.04.002 · Cited by 259 · see citing works
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. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.0763-09.2009 · Cited by 195 · see citing works
Neuroanatomy of the kisspeptin signaling system in mammals: comparative and developmental aspects
Lehman, M. N., Hileman, S. M., & Goodman, R. L. (2013) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4614-6199-9_3 · Cited by 180 · see citing works
Krajewski, S. J., Burke, M. C., Anderson, M. J., McMullen, N. T., & Rance, N. E. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2009.12.053 · Cited by 178 · see citing works
Neuroendocrine control of gonadotropin‐releasing hormone: Pulsatile and surge modes of secretion
Goodman, R. L., Herbison, A. E., Lehman, M. N., & Navarro, V. M. (2022) · Journal of Neuroendocrinology · doi:10.1111/jne.13094 · Cited by 157 · see citing works
Self-citationVida, B., Deli, L., Hrabovszky, E., Kalamatianos, T., Caraty, A., Coen, C. W., Liposits, Z., & Kalló, I. (2010) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2010.02045.x · Cited by 156 · see citing works
Chu, Z., Andrade, J., Shupnik, M. A., & Moenter, S. M. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.0352-09.2009 · Cited by 133 · see citing works
Kokay, I. C., Petersen, S. L., & Grattan, D. R. (2011) · Endocrinology · doi:10.1210/en.2010-0668 · Cited by 131 · see citing works
GnRH Pulse Generator Activity Across the Estrous Cycle of Female Mice
McQuillan, H. J., Han, S. Y., Cheong, I., & Herbison, A. E. (2019) · Endocrinology · doi:10.1210/en.2019-00193 · Cited by 127 · see citing works
Self-citationAraujo-Lopes, R., Crampton, J. R., Aquino, N. S. S., Miranda, R. M., Kokay, I. C., Reis, A. M., Franci, C. R., Grattan, D. R., & Szawka, R. E. (2014) · Endocrinology · doi:10.1210/en.2013-1889 · Cited by 119 · see citing works
Cheong, R. Y., Czieselsky, K., Porteous, R., & Herbison, A. E. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.1776-15.2015 · Cited by 114 · see citing works
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Dong, J., & Rees, D. A. (2023) · BMJ Medicine · doi:10.1136/bmjmed-2023-000548 · Cited by 123 · see citing works
Padilla, S. L., Perez, J. G., Ben-Hamo, M., Johnson, C. W., Sanchez, R. E. A., Bussi, I. L., Palmiter, R. D., & de la Iglesia, H. O. (2019) · Current Biology · doi:10.1016/j.cub.2019.01.022 · Cited by 113 · see citing works
Coming of age in the Kisspeptin Era: Sex differences, development, and puberty
Kauffman, A. S. (2010) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2010.01.017 · Cited by 106 · see citing works
17β-Estradiol Regulation of T-Type Calcium Channels in Gonadotropin-Releasing Hormone Neurons
Zhang, C., Bosch, M. A., Rick, E. A., Kelly, M. J., & Rønnekleiv, O. K. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.2962-09.2009 · Cited by 104 · see citing works
Khan, A. R., & Kauffman, A. S. (2012) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2011.02162.x · Cited by 99 · see citing works
Estrogen Permits Vasopressin Signaling in Preoptic Kisspeptin Neurons in the Female Mouse
Piet, R., Fraissenon, A., Boehm, U., & Herbison, A. E. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.4587-14.2015 · Cited by 94 · see citing works
Self-citationYeo, S.-H., & Colledge, W. H. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00188 · Cited by 76 · see citing works
Self-citationSmith, J. T. (2012) · Domestic Animal Endocrinology · doi:10.1016/j.domaniend.2011.11.003 · Cited by 55 · see citing works
Dynamics of pulsatile activities of arcuate kisspeptin neurons in aging female mice
Goto, T., Hagihara, M., & Miyamichi, K. (2023) · eLife · doi:10.7554/elife.82533 · Cited by 27 · see citing works
Potential clinical use of kisspeptin
Prague, J. K., & Dhillo, W. S. (2015) · Neuroendocrinology · doi:10.1159/000439133 · Cited by 26 · see citing works
- Authors
- Clarkson, J., d'Anglemont de Tassigny, X., Moreno, A. S., Colledge, W. H., & Herbison, A. E.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-08-27
- Volume
- 28
- Issue
- 35
- Pages
- 8691-8697
- ISSN
- 0270-6474
- 1529-2401
- Cited by
- 436
- References
- 6
- Language
- en
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