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:

Zinc finger protein too few controls the development of monoaminergic neurons

Nature Neuroscience volume 6, pages 28–33 (2003)Cite this article

Abstract

The mechanism controlling the development of dopaminergic (DA) and serotonergic (5HT) neurons in vertebrates is not well understood. Here we characterized a zebrafish mutant—too few (tof)—that develops hindbrain 5HT and noradrenergic neurons, but does not develop hypothalamic DA and 5HT neurons. tof encodes a forebrain-specific zinc finger transcription repressor that is homologous to the mammalian Fezl (forebrain embryonic zinc finger–like protein). Mosaic and co-staining analyses showed that fezl was not expressed in DA or 5HT neurons and instead controlled development of these neurons non-cell-autonomously. Both the eh1-related repressor motif and the second zinc finger domain were necessary for tof function. Our results indicate that tof/fezl is a key component in regulating the development of monoaminergic neurons in the vertebrate brain.

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: Impairment of forebrain DA and 5HT neurons in the tof mutant embryos.
Figure 2: Chromosomal linkage, molecular characterization and phenotypic rescue of tof.
Figure 3: Gain-of-function analysis of WT and mutant tof/fezl RNA.
Figure 4: tof/fezl act non-cell-autonomously.
Figure 5: Rescue of tof 5HT deficit by a non-autonomous telencephalic cue.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Kandel, E.R., Schwartz, J.H. & Jessell, T.M. Principles of Neural Science 1135 (Elsevier, New York, 1991).

  2. 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 

  3. Zetterstrom, R.H. et al. Dopamine neuron agenesis in Nurr1-deficient mice. Science 276, 248–250 (1997).

    Article  CAS  Google Scholar 

  4. Saucedo-Cardenas, O. et al. Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. Proc. Natl. Acad. Sci. USA 95, 4013–4018 (1998).

    Article  CAS  Google Scholar 

  5. 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 

  6. Simon, H.H., Saueressig, H., Wurst, W., Goulding, M.D. & O'Leary, D.D. Fate of midbrain dopaminergic neurons controlled by the engrailed genes. J. Neurosci. 21, 3126–3134 (2001).

    Article  CAS  Google Scholar 

  7. Guo, S. et al. A regulator of transcriptional elongation controls vertebrate neuronal development. Nature 408, 366–369 (2000).

    Article  CAS  Google Scholar 

  8. Dittrich, R., Bossing, T., Gould, A.P., Technau, G.M. & Urban, J. The differentiation of the serotonergic neurons in the Drosophila ventral nerve cord depends on the combined function of the zinc finger proteins Eagle and Huckebein. Development 124, 2515–2525 (1997).

    CAS  PubMed  Google Scholar 

  9. Lundell, M.J. & Hirsh, J. eagle is required for the specification of serotonin neurons and other neuroblast 7-3 progeny in the Drosophila CNS. Development 125, 463–472 (1998).

    CAS  PubMed  Google Scholar 

  10. Ye, W. et al. Distinct regulators control the expression of the mid-hindbrain organizer signal FGF8. Nat. Neurosci. 4, 1175–1181 (2001).

    Article  CAS  Google Scholar 

  11. Hynes, M., Poulsen, K., Tessier-Lavigne, M. & Rosenthal, A. Control of neuronal diversity by the floor plate: contact-mediated induction of midbrain dopaminergic neurons. Cell 80, 95–101 (1995).

    Article  CAS  Google Scholar 

  12. Guo, S. et al. Mutations in the zebrafish unmask shared regulatory pathways controlling the development of catecholaminergic neurons. Dev. Biol. 208, 473–487 (1999a).

    Article  CAS  Google Scholar 

  13. Akimenko, M.A., Ekker, M., Wegner, J., Lin, W. & Westerfield, M. Combinatorial expression of three zebrafish genes related to distal-less: part of a homeobox gene code for the head. J. Neurosci. 14, 3475–3486 (1994).

    Article  CAS  Google Scholar 

  14. Barth, K.A. & Wilson, S.W. Expression of zebrafish nk2.2 is influenced by sonic hedgehog/vertebrate hedgehog-1 and demarcates a zone of neuronal differentiation in the embryonic forebrain. Development 121, 1755–1768 (1995).

    CAS  PubMed  Google Scholar 

  15. Quint, E., Zerucha, T. & Ekker, M. Differential expression of orthologous Dlx genes in zebrafish and mice: implications for the evolution of the Dlx homeobox gene family. J. Exp. Zool. 288, 235–241 (2000).

    Article  CAS  Google Scholar 

  16. Wullimann, M.F. & Rink, E. Detailed immunohistology of Pax6 protein and tyrosine hydroxylase in the early zebrafish brain suggests role of Pax6 gene in development of dopaminergic diencephalic neurons. Brain. Res. Dev. Brain. Res. 131, 173–191 (2001).

    Article  CAS  Google Scholar 

  17. Shimoda, N. et al. Zebrafish genetic map with 2000 microsatellite markers. Genomics 58, 219–232 (1999).

    Article  CAS  Google Scholar 

  18. Geisler, R. et al. A radiation hybrid map of the zebrafish genome. Nat. Genet. 23, 86–89 (1999).

    Article  CAS  Google Scholar 

  19. Hashimoto, H. et al. Expression of the zinc finger gene fez-like in zebrafish forebrain. Mech. Dev. 97, 191–195 (2000).

    Article  CAS  Google Scholar 

  20. Yang, Z., Liu, N. & Lin, S. A zebrafish forebrain-specific zinc finger gene can induce ectopic dlx2 and dlx6 expression. Dev. Biol. 231, 138–148 (2001).

    Article  CAS  Google Scholar 

  21. Iuchi, S. Three classes of C2H2 zinc finger proteins. Cell. Mol. Life Sci. 58, 625–635 (2001).

    Article  CAS  Google Scholar 

  22. Nasevicius, A. & Ekker, S.C. Effective targeted gene knockdown in zebrafish. Nat. Genet. 26, 216–220 (2000).

    Article  CAS  Google Scholar 

  23. Strahle, U., Blader, P., Henrique, D. & Ingham, P.W. Axial, a zebrafish gene expressed along the developing body axis, shows altered expression in cyclops mutant embryos. Genes Dev. 7, 1436–1446 (1993).

    Article  CAS  Google Scholar 

  24. Jessell, T.M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nat. Rev. Genet. 1, 20–29 (2000).

    Article  CAS  Google Scholar 

  25. Matsuo-Takasaki, M., Lim, J.H., Beanan, M.J., Sato, S.M. & Sargent, T.D. Cloning and expression of a novel zinc finger gene, Fez, transcribed in the forebrain of Xenopus and mouse embryos. Mech. Dev. 93, 201–204 (2000).

    Article  CAS  Google Scholar 

  26. Bieker, J.J. Kruppel-like factors: three fingers in many pies. J. Biol. Chem. 276, 34355–34358 (2001).

    Article  CAS  Google Scholar 

  27. Chen, W., Burgess, S. & Hopkins, N. Analysis of the zebrafish smoothened mutant reveals conserved and divergent functions of hedgehog activity. Development 128, 2385–2396 (2001).

    CAS  PubMed  Google Scholar 

  28. Guo, S. et al. Development of noradrenergic neurons in the zebrafish hindbrain requires BMP, FGF8 and the homeodomain protein soulless/Phox2a. Neuron 24, 555–566 (1999b).

    Article  CAS  Google Scholar 

  29. Lawrence, P.A. & Struhl, G. Morphogens, compartments, and pattern: lessons from Drosophila? Cell 85, 951–961 (1996).

    Article  CAS  Google Scholar 

  30. Zeller, J. & Granato, M. The zebrafish diwanka gene controls an early step of motor growth cone migration. Development 126, 3461–3472 (1999).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank T. Yabe, S. Neuhauss, C. Liew, C. Ton, A. Jensen, G. Wilhelm Otto, T. Look and M. Austen for sharing their unpublished mapping information and R. Geisler and E. Goldings for providing the above contact information; M. Ekker, A. Schier, U. Strahle, P. Raymonds and S. Wilson for probes; S. Guo, K. Poulsen and L. Parker for technical advice; T. Hirano for support and comments on this work, and members of the Rosenthal lab for stimulating discussions. G.L. was supported by a long-term postdoctoral fellowship from the European Molecular Biology Organization. W.S.T. was supported by National Institutes of Health grant RR12349.

Author information

Authors and Affiliations

  1. Rinat Neuroscience Corporation, 3155 Porter Drive, Palo Alto, 94304, California, USA

    Gil Levkowitz, Jörg Zeller & Arnon Rosenthal

  2. Department of Developmental Biology, Stanford University School of Medicine, 279 Campus Drive, Stanford, 94305, California, USA

    Howard I. Sirotkin & William S. Talbot

  3. Department of Pathology, Genentech Inc., 1 DNA Way, South San Francisco, 94080, California, USA

    Dorothy French & Sarah Schilbach

  4. Division of Molecular Oncology, Biomedical Research Center, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan

    Hisashi Hashimoto

  5. Laboratory for Vertebrate Axis Formation, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuoh-ku Kobe, 650-0047, Hyogo, Japan

    Masahiko Hibi

Authors
  1. Gil Levkowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jörg Zeller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Howard I. Sirotkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dorothy French
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sarah Schilbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hisashi Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Masahiko Hibi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. William S. Talbot
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Arnon Rosenthal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gil Levkowitz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Levkowitz, G., Zeller, J., Sirotkin, H. et al. Zinc finger protein too few controls the development of monoaminergic neurons. Nat Neurosci 6, 28–33 (2003). https://doi.org/10.1038/nn979

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn979

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