Developmental Regulation of Gonadotropin-Releasing Hormone Neurons by Fibroblast Growth Factor Signaling
Abstract
GnRH neurons are central to the initiation and maintenance of reproductive function in diverse vertebrates. The formation of a functional GnRH system during development is a highly complex event that likely requires extensive guidance by neurotrophic factors. In this study, we examined whether members of the fibroblast growth factor (FGF) family are critically involved in the development of endogenous GnRH neurons. Immunocytochemistry revealed the presence of FGF receptors (FGFRs) 1, 2, and 3, but not 4, in embryonic day (E) 10.5 medial nasal placode, an area and time consistent with the first appearance of GnRH neurons in mice. Dual immunocytochemistry confirmed the presence of FGFRs 1 and 3, but not 2 and 4, in a substantial fraction of E15.5 and postnatal day (P) 3 GnRH neurons. To examine whether FGF signaling was essential for the specification of GnRH neuronal fate, a nasal explant culture that supported the in vitro emergence of GnRH neurons from E10.5 noses was established. In this system, the addition of SU5402, a FGFR antagonist, suppressed the emergence of GnRH neurons. Lastly, we investigated whether FGF signaling altered the extension of neurites in cultures of dispersed GnRH neurons. The addition of FGF2 to E15.5 and P3 GnRH neurons expressing the green fluorescent protein significantly stimulated neurite outgrowth (E15.5 and P3) and branching (P3), suggesting a regulatory role of FGFs in GnRH axon targeting. Together these results demonstrated that FGF signaling critically regulates multiple phases of development in a neuroendocrine system essential for vertebrate reproduction.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
FGFR-1 signaling through the mitogen-activated protein kinase pathway regulates neuronal migration, differentiation, survival, and cell proliferation during embryonic development.
“FGFR-1 signaling through this pathway regulates neuronal migration, differentiation, and survival, as well as cell proliferation during embryonic development.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [16]
Cites
Origin of luteinizing hormone-releasing hormone neurons
Schwanzel-Fukuda, M., & Pfaff, D. W. (1989) · Nature · doi:10.1038/338161a0 · Cited by 1,116 · see citing works
Mohammadi, M., McMahon, G., Sun, L., Tang, C., Hirth, P., Yeh, B. K., Hubbard, S. R., & Schlessinger, J. (1997) · Science · doi:10.1126/science.276.5314.955 · Cited by 1,099 · see citing works
Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome
Dodé, C., Levilliers, J., Dupont, J., Paepe, A. D., Dû, N. L., Soussi-Yanicostas, N., Coimbra, R., Delmaghani, S., Compain-Nouaille, S., Baverel, F., et al. (2003) · Nature Genetics · doi:10.1038/ng1122 · Cited by 822 · see citing works
Wray, S., Grant, P. G., & Gainer, H. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.20.8132 · Cited by 717 · see citing works
Schwanzel-Fukuda, M., Bick, D., & Pfaff, D. W. (1989) · Molecular Brain Research · doi:10.1016/0169-328x(89)90076-4 · Cited by 616 · see citing works
Mason, A. J., Hayflick, J. S., Zoeller, R. T., Young, W. S., PHILLIPS, H. S., Nikolics, K., & Seeburg, P. H. (1986) · Science · doi:10.1126/science.3024317 · Cited by 534 · see citing works
Wray, S., Nieburgs, A., & Elkabes, S. (1989) · Developmental Brain Research · doi:10.1016/0165-3806(89)90295-2 · Cited by 329 · see citing works
The status of Wnt signalling regulates neural and epidermal fates in the chick embryo
Wilson, S., Rydström, A., Trimborn, T., Willert, K., Nusse, R., Jessell, T. M., & Edlund, H. (2001) · Nature · doi:10.1038/35077115 · Cited by 323 · see citing works
Suter, K. J. (2000) · Endocrinology · doi:10.1210/en.141.1.412 · Cited by 270 · see citing works
Fibroblast Growth Factors In The Developing Central Nervous System
Ford‐Perriss, M., Abud, H., & Murphy, M. (2001) · Clinical and Experimental Pharmacology and Physiology · doi:10.1046/j.1440-1681.2001.03477.x · Cited by 264 · see citing works
Arsenite induces apoptosis in chinese hamster ovary cells by generation of reactive oxygen species
Wang, T., Kuo, C.-F., Jan, K.-Y., & Huang, H. (1996) · Journal of Cellular Physiology · doi:10.1002/(sici)1097-4652(199611)169:2 · Cited by 240 · see citing works
Sato, N. S., Katsumata, N., Kagami, M., Hasegawa, T., Hori, N., KAWAKITA, S., Minowada, S., Shimotsuka, A., Shishiba, Y., Yokozawa, M., et al. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030476 · Cited by 216 · see citing works
Prévot, V., Croix, D., Bouret, S. G., Dutoit, S., Tramu, G., Stefano, G. B., & Beauvillain, J. (1999) · Neuroscience · doi:10.1016/s0306-4522(99)00383-8 · Cited by 198 · see citing works
Specification of dorsal telencephalic character by sequential Wnt and FGF signaling
Gunhaga, L., Marklund, M., Sjödal, M., Hsieh, J.-C., Jessell, T. M., & Edlund, H. (2003) · Nature Neuroscience · doi:10.1038/nn1068 · Cited by 197 · see citing works
Expression of members of the Fgf family and their receptors during midfacial development
Bachler, M., & Neubüser, A. (2001) · Mechanisms of Development · doi:10.1016/s0925-4773(00)00518-9 · Cited by 170 · see citing works
Fueshko, S. M., & Wray, S. (1994) · Developmental Biology · doi:10.1006/dbio.1994.1319 · Cited by 169 · see citing works
Mesenchymal/Epithelial Induction Mediates Olfactory Pathway Formation
LaMantia, A., Bhasin, N., Rhodes, K., & Heemskerk, J. (2000) · Neuron · doi:10.1016/s0896-6273(00)00121-5 · Cited by 164 · see citing works
Progenitor cells of the olfactory receptor neuron lineage
Calof, A. L., Bonnin, A., Crocker, C. E., Kawauchi, S., Murray, R. C., Shou, J., & Wu, H. (2002) · Microscopy Research and Technique · doi:10.1002/jemt.10147 · Cited by 147 · see citing works
LaMantia, A., Colbert, M. C., & Linney, E. A. (1993) · Neuron · doi:10.1016/0896-6273(93)90052-s · Cited by 146 · see citing works
Kramer, P. R., & Wray, S. (2000) · Genes & Development · doi:10.1101/gad.14.14.1824 · Cited by 139 · see citing works
Allen, M. P., Zeng, C. X., Schneider, K., Xiong, X., Meintzer, M. K., Bellosta, P., Basilico, C., Varnum, B. C., Heidenreich, K. A., & Wierman, M. E. (1999) · Molecular Endocrinology · doi:10.1210/mend.13.2.0230 · Cited by 137 · see citing works
Fibroblast Growth Factor Receptors (FGFRs) Localize in Different Cellular Compartments
Johnston, C. L., Cox, H. C., Gomm, J. J., & Coombes, R. C. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.51.30643 · Cited by 133 · see citing works
Development of gonadotropin-releasing hormone-1 neurons
Wray, S. (2002) · Frontiers in Neuroendocrinology · doi:10.1016/s0091-3022(02)00001-8 · Cited by 132 · see citing works
FGF signaling regulates expression of Tbx2, Erm, Pea3, and Pax3 in the early nasal region.
Firnberg, N., & Neubüser, A. (2002) · Developmental Biology · doi:10.1006/dbio.2002.0696 · Cited by 132 · see citing works
Fibroblast Growth Factor Signaling Regulates Pillar Cell Development in the Organ of Corti
Mueller, K. L., Jacques, B. E., & Kelley, M. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-21-09368.2002 · Cited by 127 · see citing works
Stachowiak, E. K., Maher, P. A., Tucholski, J., et al. (1997) · Oncogene · doi:10.1038/sj.onc.1201057 · Cited by 124 · see citing works
Fueshko, S. M., Key, S., & Wray, S. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-07-02560.1998 · Cited by 118 · see citing works
Stachowiak, M. K., Maher, P. A., Joy, A. M., Mordechai, E., & Stachowiak, E. K. (1996) · Molecular Biology of the Cell · doi:10.1091/mbc.7.8.1299 · Cited by 115 · see citing works
Growth factor regulation of cell growth and proliferation in the nervous system
Stachowiak, M. K., Moffett, J., Maher, P. A., et al. (1997) · Molecular Neurobiology · doi:10.1007/bf02740663 · Cited by 98 · see citing works
Recent progress in the neurobiology of the vomeronasal organ
Takami, S. (2002) · Microscopy Research and Technique · doi:10.1002/jemt.10094 · Cited by 95 · see citing works
Skaper, S. D., Kee, W. J., Facci, L., et al. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0751520.x · Cited by 92 · see citing works
Development of Luteinizing Hormone Releasing Hormone Neurones
Wray, S. (2001) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.2001.00609.x · Cited by 91 · see citing works
Bless, E. P., Westaway, W. A., Schwarting, G. A., & Tobet, S. A. (2000) · Endocrinology · doi:10.1210/endo.141.3.7348 · Cited by 89 · see citing works
Paterson, J., Li, Z.-H., Wen, X., Masih-Khan, E., Chang, H., Pollett, J. B., Trudel, S., & Stewart, A. (2004) · British Journal of Haematology · doi:10.1111/j.1365-2141.2004.04814.x · Cited by 87 · see citing works
Moftah, M. Z., Downie, S. A., Bronstein, N. B., et al. (2002) · Developmental Biology · doi:10.1006/dbio.2002.0766 · Cited by 85 · see citing works
Stachowiak, M. K., Maher, P. A., Joy, A. M., et al. (1996) · Molecular Brain Research · doi:10.1016/0169-328x(96)00010-1 · Cited by 84 · see citing works
Nuclear trafficking of FGFR1: A role for the transmembrane domain
Myers, J. M., Martins, G. G., Ostrowski, J., et al. (2003) · Journal of Cellular Biochemistry · doi:10.1002/jcb.10476 · Cited by 78 · see citing works
El‐Amraoui, A., & Dubois, P. M. (2008) · Neuroendocrinology · doi:10.1159/000126490 · Cited by 73 · see citing works
Developmental aspect of the gonadotropin-releasing hormone system
Tobet, S. A., Bless, E. P., & Schwarting, G. A. (2001) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(01)00616-5 · Cited by 72 · see citing works
Voigt, P., Ma, Y. J., Gónzalez, D., et al. (1996) · Endocrinology · doi:10.1210/endo.137.6.8641214 · Cited by 69 · see citing works
Tsai, P.-I., Werner, S., & Weiner, R. I. (1995) · Endocrinology · doi:10.1210/endo.136.9.7649090 · Cited by 67 · see citing works
Self-citationAdlkofer, K., Naef, R., & Suter, U. (1997) · Journal of Neuroscience Research · doi:10.1002/(sici)1097-4547(19970915)49:6 · Cited by 59 · see citing works
Griffin, K. J. P., & Kimelman, D. (2003) · Developmental Biology · doi:10.1016/j.ydbio.2003.09.008 · Cited by 55 · see citing works
Kramer, P. R., Krishnamurthy, R., Mitchell, P. J., & Wray, S. (2000) · Endocrinology · doi:10.1210/endo.141.5.7452 · Cited by 55 · see citing works
Heryanto, B., Lipson, K. E., & Rogers, P. A. W. (2003) · Reproduction · doi:10.1530/rep.0.1250337 · Cited by 51 · see citing works
Kassner, P. D., & Berg, D. K. (1997) · Journal of Neurobiology · doi:10.1002/(sici)1097-4695(199712)33:7 · Cited by 48 · see citing works
Wetsel, W. C., Hill, D. F., & Ojeda, S. R. (1996) · Endocrinology · doi:10.1210/endo.137.6.8641215 · Cited by 41 · see citing works
Soluble Factors Guide Gonadotropin-Releasing Hormone Axonal Targeting to the Median Eminence1
Gibson, M. J., Ingraham, L., & Dobrjansky, A. (2000) · Endocrinology · doi:10.1210/endo.141.9.7656 · Cited by 32 · see citing works
Reid, S., & Ferretti, P. (2003) · Developmental Brain Research · doi:10.1016/s0165-3806(02)00635-1 · Cited by 30 · see citing works
Inhibition of FGF signaling causes expansion of the endoderm in Xenopus
Cha, S., Hwang, Y.-S., Chae, J.-P., Lee, S., Lee, H., Daar, I. O., Park, M. J., & Kim, J. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.01.019 · Cited by 21 · see citing works
Gallo, F., Morale, M. C., Tirolo, C., Testa, N., Farinella, Z., Avola, R., Beaudet, A., & Marchetti, B. (2000) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.2000.00554.x · Cited by 20 · see citing works
Rogers, M.-C., Silverman, A., & Gibson, M. J. (1998) · Experimental Neurology · doi:10.1006/exnr.1998.6805 · Cited by 11 · see citing works
Giedd (1996) · doi:10.1002/(sici)1096-9861(19960304)366:2
Flagged first, then by citations
Cited by
Sorted by citations
Boehm, U., Bouloux, P.-M., Dattani, M. T., de Roux, N., Dodé, C., Dunkel, L., Dwyer, A. A., Giacobini, P., Hardelin, J.-P., Juul, A., et al. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.112 · Cited by 874 · see citing works
Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice
Falardeau, J., Chung, W. C. J., Beenken, A., Raivio, T., Plummer, L., Sidis, Y., Jacobson-Dickman, E. E., Eliseenkova, A. V., Ma, J., Dwyer, A., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34538 · Cited by 397 · see citing works
Self-citationDigenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism
Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci29884 · Cited by 379 · see citing works
The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism
Bianco, S. D. C., & Kaiser, U. B. (2009) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2009.177 · Cited by 336 · see citing works
Pitteloud, N., Acierno, J. S., Meysing, A., Eliseenkova, A. V., Ma, J., Ibrahimi, O. A., Metzger, D. L., Hayes, F. J., Dwyer, A. A., Hughes, V. A., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600962103 · Cited by 242 · see citing works
Pitteloud, N., Meysing, A., Quinton, R., Acierno, J. S., Dwyer, A. A., Plummer, L., Fliers, E., Boepple, P., Hayes, F., Seminara, S., et al. (2006) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2006.04.021 · Cited by 198 · see citing works
Pitteloud, N., Acierno, J. S., Meysing, A. U., Dwyer, A. A., Hayes, F. J., & Crowley, W. F. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1361 · Cited by 160 · see citing works
Kim, S. ‐., Hu, Y., Cadman, S., & Bouloux, P. (2008) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2007.01627.x · Cited by 87 · see citing works
Kallmann’s syndrome, a neuronal migration defect
Cariboni, A., & Maggi, R. (2006) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-005-5604-3 · Cited by 65 · see citing works
- Authors
- Gill, J. C., Moenter, S. M., & Tsai, P.-S.
- Affiliations
- University of Colorado Boulder (US)
- University of Virginia (US)
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2004-08
- Volume
- 145
- Issue
- 8
- Pages
- 3830-3839
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W1977442072
- Cited by
- 81
- References
- 53
- Citations by year
- 2025: 1 · 2022: 1 · 2021: 4 · 2020: 4 · 2019: 2 · 2018: 1 · 2016: 1 · 2015: 3 · 2014: 2 · 2013: 5 · 2012: 5
- FWCI
- 8.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Keywords
- GnRH neurons, FGF signaling, fibroblast growth factor receptor, nasal placode, neurite outgrowth, axon targeting, neuroendocrine development, reproductive development, SU5402
- MeSH terms
- Animals, Cells, Cultured, Female, Fibroblast Growth Factors, Gonadotropin-Releasing Hormone, Mice, Inbred Strains, Neurons, Pyrroles, Reproduction, Signal Transduction, Fibroblast Growth Factor 2, Neurites, Receptors, Fibroblast Growth Factor, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
