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Coordinated regulation of cholinergic motor neuron traits through a conserved terminal selector gene

Nature Neuroscience volume 15, pages 205–214 (2012)Cite this article

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Abstract

Cholinergic motor neurons are defined by the coexpression of a battery of genes encoding proteins that act sequentially to synthesize, package and degrade acetylcholine and reuptake its breakdown product, choline. How expression of these critical motor neuron identity determinants is controlled and coordinated is not understood. We show here that, in the nematode Caenorhabditis elegans, all members of the cholinergic gene battery, as well as many other markers of terminal motor neuron fate, are co-regulated by a shared cis-regulatory signature and a common trans-acting factor, the phylogenetically conserved COE (Collier, Olf, EBF)-type transcription factor UNC-3. UNC-3 initiated and maintained expression of cholinergic fate markers and was sufficient to induce cholinergic fate in other neuron types. UNC-3 furthermore operated in negative feedforward loops to induce the expression of transcription factors that repress individual UNC-3-induced terminal fate markers, resulting in diversification of motor neuron differentiation programs in specific motor neuron subtypes. A chordate ortholog of UNC-3, Ciona intestinalis COE, was also both required and sufficient for inducing a cholinergic fate. Thus, UNC-3 is a terminal selector for cholinergic motor neuron differentiation whose function is conserved across phylogeny.

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Figure 1: unc-3 is required for expression of the cholinergic gene battery.
Figure 2: unc-3 affects A- and B-type motor neuron features but not pan-neuronal specification.
Figure 3: unc-3 is sufficient to induce cholinergic markers in other neuron types.
Figure 4: UNC-3 targets are co-regulated through consensus COE motifs.
Figure 5: unc-3 expression is required through the life of the worm.
Figure 6: Gene regulatory factors are downstream targets of unc-3.
Figure 7: The function of UNC-3 is conserved across phylogeny.

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Acknowledgements

We thank Q. Chen for expert assistance in generating transgenic strains; P. Sengupta (Brandeis University) for providing plasmids; many colleagues in the C. elegans community, particularly D. Miller (Vanderbilt University), for providing reporter strains; D. Wu and G. Minevich for bioinformatic analysis; and J. Rand and members of the Hobert laboratory for comments on the manuscript. We are grateful to Caenorhabditis Genetics Center (University of Minnesota) for providing strains. This work was funded by the Muscle Dystrophy Association and the US National Institutes of Health (R01NS039996; R01NS050266). O.H. is an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University Medical Center, New York, New York, USA

    Paschalis Kratsios & Oliver Hobert

  2. Division of Genetics, Department of Molecular and Cell Biology, Center for Integrative Genomics, Genomics and Development, University of California, Berkeley, California, USA

    Alberto Stolfi & Michael Levine

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  1. Paschalis Kratsios
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P.K. performed the C. elegans experiments under supervision of O.H. A.S. performed the C. intestinalis experiments under supervision of M.L. All authors participated in writing this paper.

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Correspondence to Paschalis Kratsios or Oliver Hobert.

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Kratsios, P., Stolfi, A., Levine, M. et al. Coordinated regulation of cholinergic motor neuron traits through a conserved terminal selector gene. Nat Neurosci 15, 205–214 (2012). https://doi.org/10.1038/nn.2989

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