Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Lmx1b is essential for the development of serotonergic neurons

Nature Neuroscience volume 6, pages 933–938 (2003)Cite this article

Abstract

The specification and differentiation of serotonergic (5-HT) neurons require both extrinsic signaling molecules and intrinsic transcription factors to work in concert or in cascade. Here we identify the genetic cascades that control the specification and differentiation of 5-HT neurons in mice. A major determinant in the cascades is an LIM homeodomain-containing gene, Lmx1b, which is required for the development of all 5-HT neurons in the central nervous system. Our results suggest that, during development of 5-HT neurons, Lmx1b is a critical intermediate factor that couples Nkx2-2–mediated early specification with Pet1-mediated terminal differentiation. Moreover, our data indicate that genetic cascades controlling the caudal and rostral 5-HT neurons are distinct, despite their shared components.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Expression patterns of Lmx1b, 5-HT and Nkx2-2 in the developing raphe nuclei.
Figure 2: Loss of 5-HT, Pet1 and other 5-HT neuronal markers in Lmx1b−/− mice.
Figure 3: Expression of Shh and transcription factors Nkx2-2 and Phox2b were similar in wild-type (+/+) and Lmx1b−/− mouse embryos (fp, floor plate).
Figure 4: Expression of Lmx1b and Gata3 in Nkx2-2−/− and Pet1−/− mutants.
Figure 5: Comparison of Lmx1b-expressing cells and Lmx1b−/− cells marked by neo staining between wild-type and Lmx1b−/− mice.
Figure 6: A model illustrating genetic pathway controlling 5-HT neuronal development.

Similar content being viewed by others

References

  1. Lauder, J.M., Wallace, J.A., Krebs, H., Petrusz, P. & McCarthy, K. In vivo and in vitro development of serotonergic neurons. Brain Res. Bull. 9, 605–625 (1982).

    Article  CAS  Google Scholar 

  2. Jacobs, B.L. & Azmitia, E.C. Structure and function of the brain serotonin system. Physiol. Rev. 72, 165–229 (1992).

    Article  CAS  Google Scholar 

  3. Halliday, G., Harding, A. & Paxinos, G. Serotonin and tachykinin systems. In The Rat Nervous System (ed. Paxinos, G.) 929–974 (Academic, Sydney, 1995).

    Google Scholar 

  4. Whitaker-Azmitia, P.M., Druse, M., Walker, P. & Lauder, J.M. Serotonin as a developmental signal. Behav. Brain Res. 73, 19–29 (1996).

    Article  CAS  Google Scholar 

  5. Lauder, J.M. Neurotransmitters as growth regulatory signals: role of receptors and second messengers. Trends. Neurosci. 16, 233–240 (1993).

    Article  CAS  Google Scholar 

  6. Basbaum, A.I. & Fields, H.L. Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu. Rev. Neurosci. 7, 309–338 (1984).

    Article  CAS  Google Scholar 

  7. Stockmeier, C.A. Neurobiology of serotonin in depression and suicide. Ann. NY Acad. Sci. 836, 220–232 (1997).

    Article  CAS  Google Scholar 

  8. Millan, M.J. Descending control of pain. Prog. Neurobiol. 66, 355–474 (2002).

    Article  CAS  Google Scholar 

  9. Hendricks, T.J. et al. Pet-1 ETS gene plays a critical role in 5-HT neuron development and is required for normal anxiety-like and aggressive behavior. Neuron 37, 233–247 (2003).

    Article  CAS  Google Scholar 

  10. Goridis, C. & Rohrer, H. Specification of catecholaminergic and serotonergic neurons. Nat. Rev. Neurosci. 3, 531–541 (2002).

    Article  CAS  Google Scholar 

  11. Ye, W., Shimamura, K., Rubenstein, J.L., Hynes, M.A. & Rosenthal, A. FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell 93, 755–766 (1998).

    Article  CAS  Google Scholar 

  12. Hynes, M. & Rosenthal, A. Specification of dopaminergic and serotonergic neurons in the vertebrate CNS. Curr. Opin. Neurobiol. 9, 26–36 (1999).

    Article  CAS  Google Scholar 

  13. Chen, H. et al. Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nat. Genet. 19, 51–55 (1998).

    Article  Google Scholar 

  14. Smidt, M.P. et al. A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b. Nat. Neurosci. 3, 337–341 (2000).

    Article  CAS  Google Scholar 

  15. Kania, A., Johnson, R.L. & Jessell, T.M. Coordinate roles for LIM homeobox genes in directing the dorsoventral trajectory of motor axons in the vertebrate limb. Cell 102, 161–173 (2000).

    Article  CAS  Google Scholar 

  16. Briscoe, J. et al. Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling. Nature 398, 622–627 (1999).

    Article  CAS  Google Scholar 

  17. Blakely, R.D. et al. Cloning and expression of a functional serotonin transporter from rat brain. Nature 354, 66–70 (1991).

    Article  CAS  Google Scholar 

  18. Bruning, G., Liangos, O. & Baumgarten, H.G. Prenatal development of the serotonin transporter in mouse brain. Cell Tissue Res. 289, 211–221 (1997).

    Article  CAS  Google Scholar 

  19. Nakamoto, H., Soeda, Y., Takami, S., Minami, M. & Satoh, M. Localization of calcitonin receptor mRNA in the mouse brain: coexistence with serotonin transporter mRNA. Brain Res. Mol. Brain Res. 76, 93–102 (2000).

    Article  CAS  Google Scholar 

  20. Pfaar, H. et al. mPet-1, a mouse ETS-domain transcription factor, is expressed in central serotonergic neurons. Dev. Genes. Evol. 212, 43–46 (2002).

    Article  CAS  Google Scholar 

  21. Hendricks, T., Francis, N., Fyodorov, D. & Deneris, E.S. The ETS domain factor Pet-1 is an early and precise marker of central serotonin neurons and interacts with a conserved element in serotonergic genes. J. Neurosci. 19, 10348–10356 (1999).

    Article  CAS  Google Scholar 

  22. Fyodorov, D., Nelson, T. & Deneris, E. Pet-1, a novel ETS domain factor that can activate neuronal nAchR gene transcription. J. Neurobiol. 34, 151–163 (1998).

    Article  CAS  Google Scholar 

  23. van Doorninck, J.H. et al. GATA-3 is involved in the development of serotonergic neurons in the caudal raphe nuclei. J. Neurosci. 19, RC12 (1999).

    Article  CAS  Google Scholar 

  24. Yamada, T., Placzek, M., Tanaka, H., Dodd, J. & Jessell, T.M. Control of cell pattern in the developing nervous system: polarizing activity of the floor plate and notochord. Cell 64, 635–647 (1991).

    Article  CAS  Google Scholar 

  25. Pattyn, A. et al. Coordinated temporal and spatial control of motor neuron and serotonergic neuron generation from a common pool of CNS progenitors. Genes Dev. 17, 729–737 (2003).

    Article  CAS  Google Scholar 

  26. Briscoe, J., Pierani, A., Jessell, T.M. & Ericson, J. A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube. Cell 101, 435–445 (2000).

    Article  CAS  Google Scholar 

  27. Chen, Z.F. et al. The paired homeodomain protein DRG11 is required for the projection of cutaneous sensory afferent fibers to the dorsal spinal cord. Neuron 31, 59–73 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank T. Jessell, J. Brunet, W. Wurst and M. Minami for reagents. We thank E.M. Johnson Jr. and M.F. Jacquin for comments on the manuscript. The project was supported by a NIH grant to Z-F.C. J.E. was supported by the Royal Swedish Academy of Sciences by a donation from the Wallenberg Foundation, The Swedish Foundation for Strategic Research, The Swedish National Research council, Brainstem Genetics: QLRT-2000-01467 and Stembridge: OLG3-CT-2002-01141. E.D. was supported by a NIH grant.

Author information

Authors and Affiliations

  1. Departments of Anesthesiology, Psychiatry, Molecular Biology and Pharmacology, School of Medicine Pain Center, Washington University, St. Louis, 63110, Missouri, USA

    Yu-Qiang Ding, Wenlin Yuan, Jun Yin & Zhou-Feng Chen

  2. Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, S-171 77, Sweden

    Ulrika Marklund & Johan Ericson

  3. Department of Neuroscience, School of Medicine, Case Western Reserve University, Cleveland, 44106, Ohio, USA

    Lauren Wegman & Evan Deneris

  4. Department of Biochemistry and Molecular Biology, University of Texas, MD Anderson Cancer Center, Houston, 77030, USA

    Randy L Johnson

Authors
  1. Yu-Qiang Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ulrika Marklund
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenlin Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jun Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lauren Wegman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Johan Ericson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Evan Deneris
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Randy L Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhou-Feng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhou-Feng Chen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ding, YQ., Marklund, U., Yuan, W. et al. Lmx1b is essential for the development of serotonergic neurons. Nat Neurosci 6, 933–938 (2003). https://doi.org/10.1038/nn1104

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1104

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing