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Ascl1 and Gsh1/2 control inhibitory and excitatory cell fate in spinal sensory interneurons

Nature Neuroscience volume 9, pages 770–778 (2006)Cite this article

Abstract

Sensory information from the periphery is integrated and transduced by excitatory and inhibitory interneurons in the dorsal spinal cord. Recent studies have identified a number of postmitotic factors that control the generation of these sensory interneurons. We show that Gsh1/2 and Ascl1 (Mash1), which are expressed in sensory interneuron progenitors, control the choice between excitatory and inhibitory cell fates in the developing mouse spinal cord. During the early phase of neurogenesis, Gsh1/2 and Ascl1 coordinately regulate the expression of Tlx3, which is a critical postmitotic determinant for dorsal glutamatergic sensory interneurons. However, at later developmental times, Ascl1 controls the expression of Ptf1a in dILA progenitors to promote inhibitory neuron differentiation while at the same time upregulating Notch signaling to ensure the proper generation of dILB excitatory neurons. We propose that this switch in Ascl1 function enables the cogeneration of inhibitory and excitatory sensory interneurons from a common pool of dorsal progenitors.

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Figure 1: Expression of Gsh1/2, Ascl1 (Mash1) and Ptf1a in the dorsal spinal cord.
Figure 2: Gsh1/2 and Ascl1 are necessary for the specification of early-born dI5 neurons.
Figure 3: Switch in cell fate of late-born neurons in Gsh1/2−/− and Ascl1−/− mice.
Figure 4: Changes in transcription factor expression in Gsh1/2−/− and Ascl1−/− mice at E12.5.
Figure 5: Altered Ptf1a expression in Gsh1/2−/− and Ascl1−/− mice.
Figure 6: Ptf1a and Ascl1 overexpression represses the dILB fate of late-born interneurons.
Figure 7: Altered Notch signaling in Ascl1 mutants.
Figure 8: Notch signaling regulates late-born sensory interneuron specification.

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Acknowledgements

The authors are grateful to S. Potter and K. Campbell for Gsh1 and Gsh2 heterozygous mice. Ascl1 heterozygous mice were provided by F. Guillemot. We thank J. Johnson, M. Bronner-Fraser and J. Boulter for Ptf1a, Cash1 and Dll1 cDNAs. Antibodies were provided by K. Campbell, T. Jessell, S. Morton, H. Edlund, T. Muller and D. Anderson. We also thank J. Johnson for sharing data before submission. E. Lamar, C. Kintner, G. Lanuza and O. Britz provided particularly helpful comments on the manuscript. This research was supported by grants from the US National Institutes of Health to M.G. and Q.M.

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Author notes

  1. Rumiko Mizuguchi and Sonja Kriks: These authors contributed equally to the work.

Authors and Affiliations

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

    Rumiko Mizuguchi, Sonja Kriks & Martyn Goulding

  2. Department of Cancer Biology, Dana Farber Cancer Institute, 1 Jimmy Fund Way, Boston, 02115, Massachusetts, USA

    Qiufu Ma

  3. Institute for Molecular Biology, Medizinische Hochschule Hannover, Carl Neuberg Strasse 1, Hannover, Germany

    Ralf Cordes & Achim Gossler

Authors
  1. Rumiko Mizuguchi
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Contributions

R.M. and S.J. undertook all the experiments for this study. R.C. and A.G. generated the Dll1hypo mice and embryos used in this study. M.G., Q.M., R.M. and S.K. contributed to the experimental planning and writing of the manuscript.

Corresponding author

Correspondence to Martyn Goulding.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Ptf1a is expressed in dorsal progenitors which have not exited the cell cycle. (PDF 1243 kb)

Supplementary Fig. 2

Genetic interactions that control inhibitory and excitatory cell fate specification in the dorsal spinal cord. (PDF 116 kb)

Supplementary Fig. 3

Mosaic Dl11 expression induces Tlx3 in presumptive dILB neurons. (PDF 1182 kb)

Supplementary Fig. 4

Reduction of dILB neurons in the dorsal horn of PS1−/− mutant. (PDF 478 kb)

Supplementary Fig. 5

Notch signaling is not activated in dorsal progenitors when early-born neurons are being generated. (PDF 666 kb)

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Mizuguchi, R., Kriks, S., Cordes, R. et al. Ascl1 and Gsh1/2 control inhibitory and excitatory cell fate in spinal sensory interneurons. Nat Neurosci 9, 770–778 (2006). https://doi.org/10.1038/nn1706

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