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Lbx1 and Tlx3 are opposing switches in determining GABAergic versus glutamatergic transmitter phenotypes

Nature Neuroscience volume 8, pages 1510–1515 (2005)Cite this article

An Erratum to this article was published on 01 December 2005

This article has been updated

Abstract

Most neurons in vertebrates make a developmental choice between two principal neurotransmitter phenotypes (glutamatergic versus GABAergic). Here we show that the homeobox gene Lbx1 determines a GABAergic cell fate in the dorsal spinal cord at early embryonic stages. In Lbx1−/− mice, the presumptive GABAergic neurons are transformed into glutamatergic cells. Furthermore, overexpression of Lbx1 in the chick spinal cord is sufficient to induce GABAergic differentiation. Paradoxically, Lbx1 is also expressed in glutamatergic neurons. We previously reported that the homeobox genes Tlx1 and Tlx3 determine glutamatergic cell fate. Here we show that impaired glutamatergic differentiation, observed in Tlx3−/− mice, is restored in Tlx3−/−Lbx1−/− mice. These genetic studies suggest that Lbx1 expression defines a basal GABAergic differentiation state, and Tlx3 acts to antagonize Lbx1 to promote glutamatergic differentiation.

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Figure 1: Lbx1 expression and its requirement for GABAergic differentiation.
Figure 2: Expansion of glutamatergic neurons in Lbx1−/− dorsal spinal cord.
Figure 3: Lbx1 suppresses glutamatergic differentiation through a Tlx3-independent pathway.
Figure 4: Tlx3 antagonizes Lbx1 to promote glutamatergic differentiation.
Figure 5: Tlx3 antagonizes Lbx1 to suppress GABAergic differentiation.
Figure 6: Cell fate switch by Lbx1 ectopic expression.

Change history

  • 21 November 2005

    This article contained a misspelling. Lhx1/2 should have read Lhx1/5 throughout the text. The PDF version of this article was corrected on 21 November 2005. Please see the PDF for details.

Notes

  1. *This article contained a misspelling. Lhx1/2 should have read Lhx1/5 throughout the text. The PDF version of this article was corrected on 21 November 2005. Please see the PDF for details.

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Acknowledgements

We thank J. Johnson, D. Rowitch, R. Puettmann-Holgado and F. Yang for critical comments on the manuscript. We dedicate this work to the memory of S. Korsmeyer, in whose laboratory the Tlx gene mutant mice were made. Q.M. is a Claudia Adams Barr Scholar and a Pew Scholar in Biomedical Sciences. This work is supported by grants from the US National Institutes of Health to Q.M. and M.G.

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Author notes

  1. Leping Cheng & Ping Luo

    Present address: Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China

Authors and Affiliations

  1. Dana-Farber Cancer Institute, Harvard Medical School, 1 Jimmy Fund Way, Boston, 02115, Massachusetts, USA

    Leping Cheng, Omar Abdel Samad, Yi Xu, Ping Luo & Qiufu Ma

  2. Department of Neurobiology, Harvard Medical School, 1 Jimmy Fund Way, Boston, 02115, Massachusetts, USA

    Leping Cheng, Omar Abdel Samad, Yi Xu, Ping Luo & Qiufu Ma

  3. Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla, 92037, California, USA

    Rumiko Mizuguchi & Martyn Goulding

  4. Department of Pathology, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, 162-8655, Tokyo, Japan

    Senji Shirasawa

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Supplementary information

Supplementary Fig. 1

Neurotransmitter phenotypes of the dorsal spinal cord neurons at embryonic stages. (PDF 1093 kb)

Supplementary Fig. 2

Tlx3 antagonizes Lbx1 to promote the glutamatergic cell fate. (PDF 185 kb)

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Cheng, L., Samad, O., Xu, Y. et al. Lbx1 and Tlx3 are opposing switches in determining GABAergic versus glutamatergic transmitter phenotypes. Nat Neurosci 8, 1510–1515 (2005). https://doi.org/10.1038/nn1569

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