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Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3

Nature Neuroscience volume 3, pages 979–985 (2000)Cite this article

Abstract

Specification of distinct neuron types in the ventral spinal cord is thought to be mediated by a graded concentration of Sonic hedgehog (Shh), a secreted signaling protein. Shh is made in the notochord, the most ventral part of the spinal cord, and in mice lacking Shh, ventral cell types are reduced or absent. The response to Shh depends on transcription factors of the Gli family, but the detailed mechanism is not understood. Here we show that Gli3 represses ventral fates in a dose-dependent manner. Whereas Shh−/− mutant mice show reductions in several classes of ventral interneurons and a complete absence of motor neurons, these cell types were rescued in Shh−/−;Gli3−/− double mutants. This rescue of the Shh null phenotype depended on the level of Gli3 function; a partial rescue was observed in Shh−/−;Gli3+/− embryos. We propose that Shh is required to antagonize Gli3, which would otherwise repress ventral fates. Differences between rostral and caudal regions suggest that other signaling molecules—in addition to Shh—may be involved in specifying ventral fates, particularly in the caudal region of the spinal cord.

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Figure 1: Shh is required to antagonize Gli3-mediated repression of neural tube development.
Figure 2: Increase in Ptc1 expression and absence of cell death in Shh−/−;Gli3−/− neural tube.
Figure 3: Expansion of Evx1/2 (V0) and En1 (V1) interneurons in Shh−/−;Gli3−/− mice.
Figure 4: Generation of V2 (Lhx3) interneurons and motor neurons (Isl1) in Shh−/−;Gli3−/− mice.
Figure 5: Presence of motor axons in Shh−/−; Gli3−/−.
Figure 6: Model for Shh and Gli function in the mammalian ventral spinal cord.

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Acknowledgements

We thank C.-c. Hui for communicating unpublished data, Peter Dempsey and Robert Coffey for the use of their Zeiss imaging system and Y. Sun for mouse husbandry. We acknowledge the help of P. Anastasiadis for the bar graphs. We also thank C.-c. Hui, B. Appel, L. Solnica-Krezel and D. Miller for discussions and suggestions on the manuscript, T. Jessell for the Evx1 and Isl1/2 antibodies, A. Karavanov and I. Dawid for the Lhx3 antibody and A. Joyner for the En1 antibody. The Mnr2, Pax7 and Nkx2.2 monoclonal antibodies developed by Susan Morton and Tom Jessell, and the Tag1 monoclonal antibody developed by M. Yamamoto were obtained from the Developmental Studies Hybridoma Bank maintained by The University of Iowa, Department of Biological Sciences, Iowa City, Iowa 52242, under contract NO1-HD-7-3263 from the NICHD. This work is supported by the NIH grant HD37489, a Basil O'Connor Award from the March of Dimes and the V Foundation.

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  1. Department of Cell Biology, Vanderbilt University Medical Center, B2120 MCN, Nashville, 37232, Tennessee , USA

    Ying Litingtung & Chin Chiang

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Correspondence to Chin Chiang.

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Litingtung, Y., Chiang, C. Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3. Nat Neurosci 3, 979–985 (2000). https://doi.org/10.1038/79916

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