Cell-autonomous FGF signaling regulates anteroposterior patterning and neuronal differentiation in the mesodiencephalic dopaminergic progenitor domain
Abstract
The structure and projection patterns of adult mesodiencephalic dopaminergic (DA) neurons are one of the best characterized systems in the vertebrate brain. However, the early organization and development of these nuclei remain poorly understood. The induction of midbrain DA neurons requires sonic hedgehog (Shh) from the floor plate and fibroblast growth factor 8 (FGF8) from the isthmic organizer, but the way in which FGF8 regulates DA neuron development is unclear. We show that, during early embryogenesis, mesodiencephalic neurons consist of two distinct populations: a diencephalic domain, which is probably independent of isthmic FGFs; and a midbrain domain, which is dependent on FGFs. Within these domains, DA progenitors and precursors use partly different genetic programs. Furthermore, the diencephalic DA domain forms a distinct cell population, which also contains non-DA Pou4f1(+) cells. FGF signaling operates in proliferative midbrain DA progenitors, but is absent in postmitotic DA precursors. The loss of FGFR1/2-mediated signaling results in a maturation failure of the midbrain DA neurons and altered patterning of the midbrain floor. In FGFR mutants, the DA domain adopts characteristics that are typical for embryonic diencephalon, including the presence of Pou4f1(+) cells among TH(+) cells, and downregulation of genes typical of midbrain DA precursors. Finally, analyses of chimeric embryos indicate that FGF signaling regulates the development of the ventral midbrain cell autonomously.
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The boundaries of the dopamine primordium are defined by transcription factor expression: the caudal extent by the Otx2/Gbx2 boundary, the rostral extent by the En1/Dbx1 boundary, and the dorsal extent by the Lmx1a/Nkx6.1 boundary.
“The caudal extent is defined by the Otx2/Gbx2 boundary coincident with the morphological mid-hindbrain boundary [74]. The rostral extent is defined by the En1/Dbx1 gene expression boundary which is located in the diencephalic region [75–78]. The dorsal extent is defined by the Lmx1a/Nkx6.1 gene expression boundary [71,79–81].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [77]
Cites
Generalized lacZ expression with the ROSA26 Cre reporter strain
Soriano, P. (1999) · Nature Genetics · doi:10.1038/5007 · Cited by 5,237 · see citing works
Dopamine neuron systems in the brain: An update
Björklund, A., & Dunnett, S. B. (2007) · Trends in Neurosciences · doi:10.1016/j.tins.2007.03.006 · Cited by 1,777 · see citing works
The substantia nigra of the human brain
Damier, P., Hirsch, É. C., Agid, Y., & Graybiel, A. M. (1999) · Brain · doi:10.1093/brain/122.8.1437 · Cited by 1,772 · see citing works
FGF and Shh Signals Control Dopaminergic and Serotonergic Cell Fate in the Anterior Neural Plate
Ye, W., Shimamura, K., Rubenstein, J. L. R., Hynes, M., & Rosenthal, A. (1998) · Cell · doi:10.1016/s0092-8674(00)81437-3 · Cited by 878 · see citing works
Midbrain development induced by FGF8 in the chick embryo
Crossley, P., Martinez, S., & Martin, G. (1996) · Nature · doi:10.1038/380066a0 · Cited by 780 · see citing works
Forebrain gene expression domains and the evolving prosomeric model
Puelles, L., & Rubenstein, J. L. R. (2003) · Trends in Neurosciences · doi:10.1016/s0166-2236(03)00234-0 · Cited by 734 · see citing works
Pathoanatomy of Parkinson’s disease
Braak, H., & Braak, E. (2000) · Journal of Neurology · doi:10.1007/pl00007758 · Cited by 693 · see citing works
Localization of monoamines in the lower brain stem
Dahlström, A. B., & Fuxé, K. (1964) · Cellular and Molecular Life Sciences · doi:10.1007/bf02147990 · Cited by 680 · see citing works
Yu, K., Xu, J.-S., Liu, Z.-H., Šošić, D., Shao, J.-S., Olson, E., Towler, D., & Ornitz, D. (2003) · Development · doi:10.1242/dev.00491 · Cited by 654 · see citing works
Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia
Meyer-Lindenberg, A., Miletich, R. S., Kohn, P. D., Esposito, G., Carson, R. E., Quarantelli, M., Weinberger, D. R., & Berman, K. F. (2002) · Nature Neuroscience · doi:10.1038/nn804 · Cited by 652 · see citing works
Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons
Ekstrand, M. I., Terzioglu, M., Galter, D., Zhu, S., Hofstetter, C., Lindqvist, E., Thams, S., Bergstrand, A., Hansson, F. S., Trifunovic, A., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0605208103 · Cited by 605 · cited 11× · see citing works
“Neither DATCre;Fgfr1cko;Fgfr2cko nor ThCre;Fgfr1cko;Fgfr2cko mutants displayed obvious alterations in their midbrain DA neurons or behavior, although controlled behavioral testing may reveal more subtle deficiencies.”
BackgroundInfluentialIdentification of intrinsic determinants of midbrain dopamine neurons
Andersson, E., Tryggvason, U., Deng, Q., Friling, S., Alekseenko, Z., Robert, B., Perlmann, T., & Ericson, J. (2006) · Cell · doi:10.1016/j.cell.2005.10.037 · Cited by 587 · see citing works
The substantia nigra of the human brain
Damier, P., Hirsch, É. C., Agid, Y., & Graybiel, A. M. (1999) · Brain · doi:10.1093/brain/122.8.1421 · Cited by 579 · see citing works
A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b
Smidt, M. P., Asbreuk, C. H. J., Cox, J. J., Chen, H., Johnson, R. L., & Burbach, J. P. H. (2000) · Nature Neuroscience · doi:10.1038/73902 · Cited by 394 · see citing works
How to make a mesodiencephalic dopaminergic neuron
Smidt, M. P., & Burbach, J. P. H. (2006) · Nature reviews. Neuroscience · doi:10.1038/nrn2039 · Cited by 356 · see citing works
SOX9 induces and maintains neural stem cells
Scott, C. E., Wynn, S. L., Sesay, A. K., Cruz, C., Cheung, M. C. H., Gómez‐Gaviro, M. V., Booth, S., Gao, B., Cheah, K. S. E., Lovell-Badge, R. H., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2646 · Cited by 356 · see citing works
Fate of Midbrain Dopaminergic Neurons Controlled by the Engrailed Genes
Simon, H. H., Saueressig, H., Wurst, W., Goulding, M., & O’Leary, D. D. M. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-09-03126.2001 · Cited by 347 · see citing works
Chi, C. L., Martı́nez, S., Wurst, W., & Martin, G. R. (2003) · Development · doi:10.1242/dev.00487 · Cited by 343 · see citing works
Two lineage boundaries coordinate vertebrate apical ectodermal ridge formationPreprint
Kimmel, R. A., Turnbull, D. H., Blanquet, V., Wurst, W., Loomis, C. A., & Joyner, A. L. (2000) · Genes & Development · doi:10.1101/gad.14.11.1377 · Cited by 341 · see citing works
Ono, Y., Nakatani, T., Sakamoto, Y., Mizuhara, E., Minaki, Y., Kumai, M., Hamaguchi, A., Nishimura, M., Inoue, Y., Hayashi, H., et al. (2007) · Development · doi:10.1242/dev.02879 · Cited by 331 · see citing works
Smidt, M. P., Smits, S. M., Bouwmeester, H., Hamers, F. P. T., van der Linden, A. J. A., Hellemons, A. J. C. G. M., Graw, J., & Burbach, J. P. H. (2004) · Development · doi:10.1242/dev.01022 · Cited by 317 · see citing works
Ferri, L., Lin, W., Mavromatakis, Y. E., Wang, J. C., Sasaki, H., Whitsett, J. A., & Ang, S. (2007) · Development · doi:10.1242/dev.000141 · Cited by 290 · see citing works
Pax-6 functions in boundary formation and axon guidance in the embryonic mouse forebrain
Mastick, G. S., Davis, N. M., Andrews, G. L., & Easter, S. S. (1997) · Development · doi:10.1242/dev.124.10.1985 · Cited by 269 · see citing works
Xu, Z. L. J., & Ornitz, D. M. (2000) · Development · doi:10.1242/dev.127.9.1833 · Cited by 264 · see citing works
Prakash, N., Brodski, C., Naserke, T., Puelles, E., Gogoi, R., Hall, A. C., Panhuysen, M., Echevarrı́a, D., Sussel, L., Weisenhorn, D. M. V., et al. (2005) · Development · doi:10.1242/dev.02181 · Cited by 254 · see citing works
Early Anterior/Posterior Patterning of the Midbrain and Cerebellum
Liu, A., & Joyner, A. L. (2001) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.24.1.869 · Cited by 248 · see citing works
Neurogenin 2 is required for the development of ventral midbrain dopaminergic neurons
Kele, J., Simplicio, N., Ferri, L., Mira, H., Guillemot, F., Arenas, E., & Ang, S. (2006) · Development · doi:10.1242/dev.02223 · Cited by 247 · see citing works
Partanen, J. M., Schwartz, L., & Rossant, J. (1998) · Genes & Development · doi:10.1101/gad.12.15.2332 · Cited by 224 · see citing works
Self-citationTransgenic expression of Cre recombinase from the tyrosine hydroxylase locus
Lindeberg, J., Usoskin, D., Bengtsson, H., Gustafsson, A., Kylberg, A., Söderström, S., & Ebendal, T. (2004) · genesis · doi:10.1002/gene.20065 · Cited by 211 · see citing works
Chung, S., Leung, A., Han, B.-S., Chang, M., Moon, J.-I., Kim, C., Hong, S., Pruszak, J., Ole Isacson, A., & Kim, K. S. (2009) · Cell stem cell · doi:10.1016/j.stem.2009.09.015 · Cited by 209 · see citing works
Albéri, L., Sgadó, P., & Simon, H. H. (2004) · Development · doi:10.1242/dev.01128 · Cited by 192 · see citing works
A Segmental Morphological Paradigm for Understanding Vertebrate Forebrains (Part 1 of 2)
Puelles, L. (2008) · Brain Behavior and Evolution · doi:10.1159/000113282 · Cited by 188 · see citing works
Maxwell, S. L., Ho, H. H., Kuehner, E., Zhao, S., & Li, M. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.03.028 · Cited by 187 · see citing works
Trokovic, R., Trokovic, N., Hernesniemi, S., Pirvola, U., Weisenhorn, D. M. V., Rossant, J., McMahon, A. P., Wurst, W., & Partanen, J. M. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg169 · Cited by 184 · see citing works
Self-citationTranscriptional control of midbrain dopaminergic neuron development
Ang, S. (2006) · Development · doi:10.1242/dev.02501 · Cited by 175 · see citing works
Farkas, L. M., Dünker, N., Roussa, E., Unsicker, K., & KRIEGLSTEIN, K. G. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-12-05178.2003 · Cited by 174 · see citing works
Andersson, E., Jensen, J. B., Parmar, M., Guillemot, F., & Björklund, A. (2006) · Development · doi:10.1242/dev.02224 · Cited by 166 · see citing works
Dynamics of the dopaminergic system as a key component to the understanding of depression
Yadid, G., & Friedman, A. (2008) · Progress in brain research · doi:10.1016/s0079-6123(08)00913-8 · Cited by 160 · see citing works
Pax6 defines the di-mesencephalic boundary by repressing En1 and Pax2
Matsunaga, E., Araki, I., & Nakamura, H. (2000) · Development · doi:10.1242/dev.127.11.2357 · Cited by 148 · see citing works
Retinoic acid counteracts developmental defects in the substantia nigra caused by Pitx3 deficiency
Jacobs, F. M. J., Smits, S. M., Noorlander, C. W., von Oerthel, L., van der Linden, A. J. A., Burbach, J. P. H., & Smidt, M. P. (2007) · Development · doi:10.1242/dev.02865 · Cited by 141 · see citing works
In situ hybridization and the three-dimensional reconstrt1ction of serial sections
Wilkinson, D. G., & Green, J. (1990) · doi:10.1093/oso/9780199630882.003.0009 · Cited by 141 · see citing works
Identification of midbrain floor plate radial glia-like cells as dopaminergic progenitors
Bonilla, S., Hall, A. C., Pinto, L., Attardo, A., Götz, M., Huttner, W. B., & Arenas, E. (2008) · Glia · doi:10.1002/glia.20654 · Cited by 136 · see citing works
Genetic networks controlling the development of midbrain dopaminergic neurons
Prakash, N., & Wurst, W. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.113464 · Cited by 136 · see citing works
Engrailed defines the position of dorsal di-mesencephalic boundary by repressing diencephalic fate
Araki, I., & Nakamura, H. (1999) · Development · doi:10.1242/dev.126.22.5127 · Cited by 135 · see citing works
Blaess, S., Bodea, G. O., Kabanova, A., Chanet, S., Mugniery, E., Derouiche, A., Stephen, D., & Joyner, A. L. (2011) · Neural Development · doi:10.1186/1749-8104-6-29 · Cited by 133 · see citing works
Basson, M. A., Echevarrı́a, D., Ahn, C. P., Sudarov, A., Joyner, A. L., Mason, I. J., Martı́nez, S., & Martin, G. R. (2008) · Development · doi:10.1242/dev.011569 · Cited by 133 · see citing works
Developmental origin and fate of meso-diencephalic dopamine neurons
Smits, S. M., Burbach, J. P. H., & Smidt, M. P. (2006) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2005.12.003 · Cited by 123 · see citing works
Joksimovic, M., Anderegg, A., Roy, A., Campochiaro, L., Yun, B., Kittappa, R., McKay, R., & Awatramani, R. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0904285106 · Cited by 121 · see citing works
Nakatani, T., Minaki, Y., Kumai, M., & Ono, Y. (2007) · Development · doi:10.1242/dev.02870 · Cited by 108 · see citing works
Andersson, E. R., Prakash, N., Čajánek, L., Minina, E., Bryja, V., Bryjová, L., Yamaguchi, T. P., Hall, A. C., Wurst, W., & Arenas, E. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003517 · Cited by 105 · see citing works
Saarimäki-Vire, J., Peltopuro, P., Lahti, L., Naserke, T., Blak, A., Weisenhorn, D. V. V., Yu, K., Ornitz, D., Wurst, W., & Partanen, J. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.0192-07.2007 · Cited by 103 · see citing works
Self-citationGata2is a tissue-specific post-mitotic selector gene for midbrain GABAergic neurons
Achim, K., Haugas, M., Lilleväli, K., Guimerá, J., Wurst, W., Salminen, M., & Partanen, J. M. (2008) · Development · doi:10.1242/dev.029900 · Cited by 101 · see citing works
Self-citationCircadian Rhythms, the Mesolimbic Dopaminergic Circuit, and Drug Addiction
McClung, C. A. (2007) · The Scientific World JOURNAL · doi:10.1100/tsw.2007.213 · Cited by 99 · see citing works
Transcriptional regulation of mesencephalic dopaminergic neurons: The full circle of life and death
Alavian, K. N., Scholz, C., & Simon, H. H. (2007) · Movement Disorders · doi:10.1002/mds.21640 · Cited by 91 · see citing works
Marı́n, F., Herrero, M. T., Vyas, S., & Puelles, L. (2005) · Developmental Dynamics · doi:10.1002/dvdy.20467 · Cited by 90 · see citing works
Holzschuh, J., Hauptmann, G., & Driever, W. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-13-05507.2003 · Cited by 85 · see citing works
Midbrain dopaminergic neurons: control of their cell fate by the engrailed transcription factors
Simon, H. H., Thuret, S., & Alberi, L. A. (2004) · Cell and Tissue Research · doi:10.1007/s00441-004-0973-8 · Cited by 82 · see citing works
Fgfr1-dependent boundary cells between developing mid- and hindbrain.
Trokovic, R., Jukkola, T., Saarimäki, J., Peltopuro, P., Naserke, T., Weisenhorn, D. V. V., Trokovic, N., Wurst, W., & Partanen, J. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2004.11.024 · Cited by 82 · see citing works
Self-citationSato, T., & Joyner, A. L. (2009) · Development · doi:10.1242/dev.041210 · Cited by 81 · see citing works
Nkx6-1 controls the identity and fate of red nucleus and oculomotor neurons in the mouse midbrain
Prakash, N., Puelles, E., Freude, K., Trümbach, D., Omodei, D., Salvio, M. D., Sussel, L., Ericson, J., Sander, M., Simeone, A., et al. (2009) · Development · doi:10.1242/dev.031781 · Cited by 80 · see citing works
Klejbor, I., Myers, J. M., Hausknecht, K., Corso, T. D., Gambino, A. S., Moryś, J., Maher, P., Hard, R., Richards, J. C., Stachowiak, E., et al. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03754.x · Cited by 76 · see citing works
A role for midbrain arcs in nucleogenesis
Agarwala, S., & Ragsdale, C. W. (2002) · Development · doi:10.1242/dev.00179 · Cited by 68 · see citing works
FGF signalling pathways in development of the midbrain and anterior hindbrain
Partanen, J. M. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04463.x · Cited by 66 · see citing works
Self-citationTGF-β promotes survival on mesencephalic dopaminergic neurons in cooperation with Shh and FGF-8
Roussa, E., Farkas, L. M., & KRIEGLSTEIN, K. G. (2004) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.03.006 · Cited by 65 · see citing works
Function of Wnts in Dopaminergic Neuron Development
Castelo‐Branco, G., & Arenas, E. (2006) · Neurodegenerative Diseases · doi:10.1159/000092086 · Cited by 64 · see citing works
Mavromatakis, Y. E., Lin, W., Metzakopian, E., Ferri, L., Yan, C. H., Sasaki, H., Whisett, J., & Ang, S. (2010) · Mechanisms of Development · doi:10.1016/j.mod.2010.11.002 · Cited by 61 · see citing works
Jukkola, T., Lahti, L., Naserke, T., Wurst, W., & Partanen, J. M. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.05.002 · Cited by 56 · see citing works
Self-citationAiravaara, M., Mijatovic, J., Vihavainen, T., Piepponen, P. T., Saarma, M., & Ahtee, L. (2006) · Synapse · doi:10.1002/syn.20245 · Cited by 51 · see citing works
Howard Henry Tooth (1856-1925)
Pearce, J. (2000) · Journal of Neurology · doi:10.1007/s004150050002 · Cited by 46 · see citing works
Fedtsova, N. G., & Turner, E. E. (2001) · Mechanisms of Development · doi:10.1016/s0925-4773(01)00399-9 · Cited by 46 · see citing works
Expression of Fgf receptors 1, 2, and 3 in the developing mid‐ and hindbrain of the mouse
Blak, A. A., Naserke, T., Weisenhorn, D. M. V., Prakash, N., Partanen, J. M., & Wurst, W. (2005) · Developmental Dynamics · doi:10.1002/dvdy.20386 · Cited by 46 · see citing works
Self-citationReimers, D., López-Toledano, M. A., Mason, I. J., Cuevas, P., Redondo, C., Herranz, A. S., Lobo, M. V. T., & Bazán, E. (2001) · Neurological Research · doi:10.1179/016164101101199090 · Cited by 44 · see citing works
Alavian, K. N., Sgadó, P., Alberi, L. A., Subramaniam, S., & Simon, H. H. (2009) · Neural Development · doi:10.1186/1749-8104-4-11 · Cited by 42 · see citing works
Eaton, M. J., Gudehithlu, K. P., Quach, T., Silvia, C. P., Hadjiconstantinou, M., & Neff, N. H. (1993) · The Journal of Comparative Neurology · doi:10.1002/cne.903370409 · Cited by 34 · see citing works
Lahti, L., Saarimäki‐Vire, J., Rita, H. J., & Partanen, J. M. (2010) · Developmental Biology · doi:10.1016/j.ydbio.2010.11.008 · Cited by 33 · see citing works
Self-citationWang, S., & Turner, E. E. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1977-10.2010 · Cited by 14 · see citing works
Kritzer (1997) · doi:10.1002/(sici)1096-9861(19970310)379:2
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- Authors
- Lahti, L., Peltopuro, P., Piepponen, T. P., & Partanen, J.
- Affiliations
- University of Helsinki (FI)
- Division of Pharmacology and Toxicology, Faculty of Pharmacy, PO Box 56, 00014 University of Helsinki, Helsinki, Finland.
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2012-03-01
- Volume
- 139
- Issue
- 5
- Pages
- 894-905
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W1997187913
- Cited by
- 34
- References
- 78
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 1 · 2018: 1 · 2017: 4 · 2015: 6 · 2014: 7 · 2013: 4 · 2012: 3
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- FGF signaling, anterior-posterior patterning, neuronal differentiation, FGF8, diencephalon, POU4F1, chimeric embryos, midbrain development
- MeSH terms
- Animals, Cell Differentiation, Diencephalon, Embryo, Mammalian, Female, Fibroblast Growth Factors, Mesencephalon, Morphogenesis, Pregnancy, Stem Cells, Tretinoin, Signal Transduction, Receptors, Fibroblast Growth Factor, Homeodomain Proteins, Gene Expression Regulation, Developmental, Extracellular Signal-Regulated MAP Kinases, Mice, Dopaminergic Neurons
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